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Metabolic Treatment of Cancer: Intermediate Results of a Prospective Case Series



The combination of hydroxycitrate and lipoic acid has been demonstrated by several laboratories to be effective in reducing murine cancer growth. All patients had failed standard chemotherapy and were offered only palliative care by their referring oncologist. Karnofsky status was between 50 and 80. Life expectancy was estimated to be between 2 and 6 months. Ten consecutive patients with chemoresistant advanced metastatic cancer were offered compassionate metabolic treatment. They were treated with a combination of lipoic acid at 600 mg i.v. (Thioctacid), hydroxycitrate at 500 mg t.i.d. (Solgar) and low-dose naltrexone at 5 mg (Revia) at bedtime. Primary sites were lung carcinoma (n=2), colonic carcinoma (n=2), ovarian carcinoma (n=1), esophageal carcinoma (n=1), uterine sarcoma (n=1), cholangiocarcinoma (n=1), parotid carcinoma (n=1) and unknown primary (n=1). The patients had been heavily pre-treated. One patient had received four lines of chemotherapy, four patients three lines, four patients two lines and one patient had received radiation therapy and chemotherapy. An eleventh patient with advanced prostate cancer resistant to hormonotherapy treated with hydroxycitrate, lipoic acid and anti-androgen is also reported. One patient was unable to receive i.v. lipoic acid and was switched to oral lipoic acid (Tiobec). Toxicity was limited to transient nausea and vomiting. Two patients died of progressive disease within two months. Two other patients had to be switched to conventional chemotherapy combined with metabolic treatment, one of when had a subsequent dramatic tumor response. Disease in the other patients was either stable or very slowly progressive. The patient with hormone-resistant prostate cancer had a dramatic fall in Prostate-Specific Antigen (90%), which is still decreasing. These very primary results suggest the lack of toxicity and the probable efficacy of metabolic treatment in chemoresistant advanced carcinoma. It is also probable that metabolic treatment enhances the efficacy of cytotoxic chemotherapy. These results are in line with published animal data. A randomized clinical trial is warranted.
Metabolic Treatment of Cancer: Intermediate Results of a
Prospective Case Series
Laurent Schwartz 1,2, Ludivine Buhler3, Philippe Icard4, Hubert Lincet
and Jean-Marc Steyaert1
1Ecole Polytechnique, Palaiseau, France;
2Assistance Publique des hôpitaux de Paris (AH-HP)
3Faculté de médecine, C.H.U. Lille, France;
4Chirurgie thoracique, C.H.U Caen, Côte de Nacre, France;
Correspondence to: L. Schwartz, Ecole Polytechnique Laboratoire
LIX, 91128 Palaiseau, France. E-mail:
Key Words: Hydroxycitrate, alpha lipoic acid, low-dose naltrexone,
metabolism, advanced cancer.
Abstract. Background: The combination of hydroxycitrate and lipoic acid has
been demonstrated by several laboratories to be effective in reducing murine
cancer growth.
Patients and Methods: All patients had failed standard chemotherapy and
were offered only palliative care by their referring oncologist. Karnofsky
status was between 50 and 80. Life expectancy was estimated to be between
2 and 6 months. Ten consecutive patients with chemoresistant advanced
metastatic cancer were offered compassionate metabolic treatment. They
were treated with a combination of lipoic acid at 600 mg i.v. (Thioctacid),
hydroxycitrate at 500 mg t.i.d (Solgar) and low-dose naltrexone at 5 mg
(Revia) at bedtime. Primary sites were lung carcinoma (n=2), colonic
carcinoma (n=2), ovarian carcinoma (n=1), esophageal carcinoma (n=1),
uterine sarcoma (n=1), cholangiocarcinoma (n=1), parotid carcinoma (n=1)
and unknown primary (n=1). The patients had been heavily pretreated. One
patient had received four lines of chemotherapy, four patients three lines, four
patients two lines and one patient had received radiation therapy and
chemotherapy. An eleventh patient with advanced prostate cancer resistant to
hormonotherapy treated with hydroxycitrate, lipoic acid and anti-androgen is
also reported.
Results: One patient was unable to receive i.v. lipoic acid and was switched to
oral lipoic acid (Tiobec). Toxicity was limited to transient nausea and vomiting.
Two patients died of progressive disease within two months. Two other
patients had to be switched to conventional chemotherapy combined with
metabolic treatment, one of when had a subsequent dramatic tumor
response. Disease in the other patients was either stable or very slowly
progressive. The patient with hormone-resistant prostate cancer had a
dramatic fall in Prostate-Specific Antigen (90%), which is still decreasing.
Conclusion: These very primary results suggest the lack of toxicity and the
probable efficacy of metabolic treatment in chemoresistant advanced
carcinoma. It is also probable that metabolic treatment enhances the efficacy
of cytotoxic chemotherapy. These results are in line with published animal
data. A randomized clinical trial is warranted.
The alteration of glucose metabolism in cancer was first described by
Warburg almost 90 years ago (1). In cancer cells, there is an increased
uptake of glucose which cannot be degraded via the Krebs cycle. Metabolic
fluxes are then diverted toward the synthesis of lactate and the pentose
phosphate shunt. Pentose phosphate is necessary for the synthesis of DNA
and RNA (2-5). In cancer cells, the Krebs cycle is also abnormal, with citrate
flowing outside the mitochondria to contribute to lipid synthesis.
Our laboratory has screened large numbers of compounds, most of
which have been clearly targeted at the altered metabolic pathways frequently
present in cancer cells due to the Warburg effect (6-8).
Given this, it is logical to target the altered metabolic pathways in
order to inhibit cancer growth. As a consequence, it is not surprising that a
rather large number of potential inhibitors of glycolysis have been evaluated
both in vitro and in vivo as potential anticancer drugs (for reviews see 8, 9).
Our first study (1) utilized a library of 27 compounds known to affect
glucose metabolism drawn from a detailed literature analysis. In vitro tests
were conducted on four cell lines at concentrations consistent with human
dosage levels in order to assess antiproliferative activity. From the effective
compounds, further in vitro testing was conducted on binary combinations and
the seven combinations that showed significant activity in the in vitro tests
were then evaluated in vivo against mice bearing a syngeneic MBT-2 bladder
tumor. The most effective treatment was a combination of hydroxycitrate
(HCA) and alpha-lipoic acid (α-LA), which we have designated as
METABLOCTM. The efficacy of this combination was confirmed in mice with
B16-F10 melanoma and LL/2 Lewis lung carcinoma. The HCA/α-LA
combination slowed tumor growth and increased survival, with an efficacy
similar to that of conventional chemotherapy. These encouraging results have
since been repeated in a second laboratory (2).
The first human toxicity trials were conducted using increasing dosage
of oral α-LA and HCA in addition to standard anticancer cytotoxic
chemotherapy. Between 2009 and 2011, 11 patients with histologically proven
malignant disease were treated according to the standard protocol in use for
their cancer type and stage (11). In addition to their normal chemotherapeutic
regimen, a combination of α-LA and HCA was administered. Informed consent
was obtained and efficacy results and side-effects were registered. The
minimum oral dose of α-LA administered was 0.4 g/day, and the maximum
dose was 1.8 g/day. The minimum dose of HCA was 1.2 g/day and the
maximum dose was 3 g/day.
The recorded side-effects were related to the respective
chemotherapies administered, except for gastrointestinal disorders of mild
intensity. Three patients out of five treated with higher doses of α-LA and
HCA, 1.8 g/day and 3 g/day, respectively, had a number of grade 1 to 3 side-
effects, including stomach pain, diarrhea and nausea, and two patients
reported weight loss.
These side-effects disappeared on using proton pump inhibitors or by
reducing the dose. Seven patients tolerated the α-LA plus HCA treatment
without side-effects. Two of these patients were administered proton pump
inhibitors as part of their treatment, but the other five had no accompanying
treatment. The minimum duration of treatment was two months, while the
maximum duration was 44 months.
Most of the patients receiving treatment for more than six months
displayed partial regression or stabilization. Of the eleven patients, disease in
five was characterized by partial regression, three by stable disease, and
three by progression.
One patient affected by a pancreatic adenocarcinoma with liver
metastases displayed tumor regression during a few months. After she
decided to stop her treatment, she died. She had survived 18 months after
starting this treatment (10). A patient with parotid gland carcinoma also
responded to this therapy, with regression of primary tumor and metastases.
However, the cancer finally recurred. Another patient is alive and well at four
years after the diagnosis of widely metastatic bulky peritoneal metastasis of a
colonic carcinoma (11).
In the meantime, Berkson and al. (12, 13) treated four patients with
pancreatic cancer with a combination of α- LA and naltrexone. The results
were strikingly positive, and the first patient treated was alive and well 78
months following the initiation of treatment.
An other group synthesized, CPI-613, an α-LA analog, and reported
activity in one patient with metastatic pancreatic adenocarcinoma (14).
We decided to test if metabolic treatment alone (a combination of α-
LA, HCA and low dose-naltrexone) was safe and effective in refractory end
stage cancer.
In this series, all patients had failed standard chemotherapy and were
offered only palliative care by their oncologists. Karnofsky status was between
50 and 80. Life expectancy was estimated to be between two and six months.
Ten patients with chemoresistant advanced metastatic cancer were
treated with a combination of 600 mg i.v. α-LA (Thioctacid; Meda Pharma
GmbH & Co. KG, Bad Homburg, Germany), 500 mg hydroxycitrate t.i.d
(Solgar, Leonia, NJ 07605, USA) and low-dose naltrexone (5 mg; Revia,
Bristol-Myers Squibb, Rueil-Malmaison cdx, France) at bedtime. Primary sites
were lung carcinoma (n=2), colonic carcinoma (n=2), ovarian carcinoma
(n=1), esophageal carcinoma (n=1), uterine sarcoma (n=1) and
cholangiocarcinoma (n=1) and parotid carcinoma (n=1) and unknown primary
The patients had been heavily pretreated. One patient had received
four lines of chemotherapy, four patients: three lines, four patients: two lines
respectively, one patient radiation therapy and chemotherapy.
An eleventh patient with hormone refractory prostate cancer treated
himself, without medical advice, with HCA, α-LA and anti-androgen. His case
is reported below.
Case 1. A 58-year-old lady had a right inferior lobectomy (07/2011) for a
pT3N0 stage IIB papillary adenocarcinoma. Despite adjuvant chemotherapy
(cisplatin, gemzar), she developed tumor recurrence and multiple lung
metastases (02/2012). Alimta was first ineffective and followed by an
ineffective experimental association of drugs (phase Ib trial of an oral inhibitor
Phosphoinositide 3-kinase (PI3K) and Mitogen-activated protein kinase kinase
(MEK)). After failure in the trial, the patient was left with no therapeutic option
but best supportive care. She was told by her referring oncologist in 12/2012,
that she had less than three months to live. Because of extensive lung
metastases, she was receiving oxygen (3 L/min).
Since mid-January 2013 (for chest Computed Tomography see figure
1), she has been treated with i.v. α-LA at 600 mg/day, HCA at 500 mg three
times a day, naltrexone at 4.5 mg/day, bicarbonate at 7g/d, medrol
(methylprednisolone) at 16 mg/day and inexium (esomeprazole) at 40 mg/day.
No side-effects have been reported. Radiological evaluation (Positron
Emission Tomography (PET) scan 05/2013, Computed Tomography (CT) scan
06/2013) showed stabilization of the disease. Late in 09/2013, she developed
acute pulmonary distress, no CT scan was performed, and she was
transferred to palliative care. She was then switched to chemotherapy and is
alive in 12/13.
Case 2. A 64-year-old former smoker had been diagnosed in 04/2012 with a
stage IV lung adenocarcinoma, with brain and bone metastases. Between
04/2012 and 01/2013 he was treated with carboplatin and bevacizumab. In
01/2013, bevacizumab was switched to pemetrexed because of tumor
progression. The brain metastases were treated by radiation therapy in
02/2013. He started i.v. α-LA doses and HCA in late 04/2013. He died of
tumor progression seven weeks later.
Case 3. The third patient had a colonic carcinoma with multiple liver
metastases. She failed three lines of chemotherapy with cetuximab, vectibix
and one experimental treatment. She was left with no therapeutic options.
She started metabolic treatment at 03/2013. The first CT scan 05/2013
demonstrated tumor progression but the next one, one month later showed
stable disease. She had to be treated by radiation therapy because of
extrinsic compression of bile ducts. She is alive in 12/13.
Case 4. The fourth patient was diagnosed with colonic adenocarcinoma T4N1
M1 with multiple liver metastases in 11/2011. Chemotherapy with 5-
fluorouracil (5 FU) and oxaliplatin was ineffective. Oxaliplatin was switched to
paclitaxel in 01/2013 and was also ineffective. He started metabolic treatment
in 04/2013 and died two months later because of tumor progression.
Case 5. This 53-year-old lady was diagnosed in 09/2008 with metastatic
ovarian carcinoma. She was first treated with paclitaxel, carboplatin and
bevacizumab, then bevacizumab, caelix and cyclophosphamide, followed by
immunotherapy. In 03/2013, she started metabolic treatment. In 05/2013, a
pleural effusion was responsible for dyspnea. She started paclitaxel-based
chemotherapy with oral metabolic therapy. The ovarian tumor has grown
slowly since. A pleurodesis was performed late 09/2013. She died in 12/13 of
tumor progression.
Case 6. The sixth patient is a 58-year-old man who had been diagnosed in
10/2011 with an adenocarcinoma of the esophagus with multiples metastases
to the liver and lymph nodes. FOLFOX (a combination of folinic Acid, 5 FU an
oxaliplatin) was stopped in 04/2012 due to a complete response. Because of
local and metastatic relapse, metabolic treatment was started in 03/2013 but
failed to prevent massive tumor growth. In 05/2013, treatment was switched to
chemotherapy with fluorouracil and irinotecan in combination with oral α-LA,
HCA and naltrexone. It resulted in massive tumor shrinkage. The last CT scan
of late 11/2013 demonstrated partial regression of the liver metastases.
Gastroscopy was negative. Karnofsky status was 90. Figure 2 shows the
dramatic reduction of the tumor mass after a combination of chemotherapy
and metabolic treatment.
Case 7. This 69-year-old lady was diagnosed with a sarcoma of the uterus in
2007. She was treated with surgery, postoperative radiation therapy and
chemotherapy. She developed severe radiation enteritis resulting both in
weight loss and in multiple surgeries. In 01/2013, the tumor relapsed with 14
different brain metastases, one of 30 mm in the frontal lobe. She was treated
with palliative radiation therapy (30 Gy in 10 fractions). Living in a remote
area, she could not undergo daily i.v. infusion. Because of low weight (45 kg),
the doses were reduced. In early March 2013, she started oral R α-LA at 650
mg/per day, HCA at 250 mg t.i.d and naltrexone at 5 mg. The last Magnetic
Resonance Imaging (MRI) dated 18th June showed almost complete
disappearance of brain lesions. She is free of symptoms but had two episodes
of seizure in late 09/2013. As of late 2013, she is living a normal life.
Case 8. This 53-year-old lady had a partial hepatectomy in 02/2012 for a
T1N1M0 cholangiocarcinoma. Despite FOLFOX, she developed multiple lung
metastases in 6/12. Sutent was ineffective. She started metabolic treatment in
03/2013 with i.v. α-LA at 600 mg, HCA at 500 mg t.i.d. and 5 mg naltrexone
associated with sutent until 05/2013. CT scan showed no progression of the
disease. The last PET scan of late August 2013 showed stabilization of the
lung metastases but the appearance of small abdominal lymph node
metastases (see Figure 3). In 11/2013 there was a limited tumor progression
and xeloda was added.
Case 9. The ninth patient is a 63-year-old man who was diagnosed in 08/2010
with metastatic adenocarcinoma to the bone and liver. No primary lesion was
found. His tumor responded well to local radiation therapy and FOLFOX. In
01/2012, a PET scan was negative but demonstrated relapse in 06/2012.
Palliative radiation therapy was effective and chemotherapy (gemcitabine)
was started in 01/2013. Because of grade III toxicity, the patient stopped
chemotherapy and switched to metabolic treatment in 04/2013. A PET scan in
July 2013 showed the appearance of a new liver metastasis and regression of
known metastatic lesions. In 10/2013, a PET scan showed increased tumor
uptake in the liver; the patient was clinically well. He started a 40 days fast
and was doing well in 12/2013.
Case 10. This 35-year-old lady presented with a parotid tumor which was first
thought to be a pleomorphic adenoma in 01/2010. The tumor relapsed in the
tumor bed in 11/2011. The draining lymph nodes were involved. Further
surgery demonstrated parotid carcinoma. Multiple lung metastases were
diagnosed in 10/2012. Chemotherapy with carboplatin and paclitaxel was
ineffective. The addition of bevacizumab had no positive effect. In 06/2013,
she started metabolic treatment. She experienced nausea and vomiting and
had to switch two months later to a better tolerated oral form. In 09/2013, a CT
scan demonstrated stabilization of disease.
Case 11. A 73-year-old patient had been diagnosed in 2005 with a high-grade
prostate adenocarcinoma T3N0M0. Despite surgery and postoperative
radiation therapy, the PSA level remained elevated. Treatment with decapeptyl
was effective up to 01/2013. Because of marked increase in PSA, casodex
was added. The patient was informed of the dismal prognosis of the disease.
He decided by himself to add 600 mg α-LA combined with HCA at 500 mg/day
associated with casodex and decapeptyl. The level of PSA is shown in Figure
Cancer is not only a disease of the genome but also a disease of the
metabolism. Since the work of the Nobel Prize winner Otto Warburg, we know
that the metabolism of cancerous cells clearly differs from that of normal cells
(3, 15, 16). This is the actual basis for PET imagery, in which the i.v. injection
of a radioactive substance similar to glucose is used to visualize the cancer
and its metastases (17). This fact, which had long been forgotten, is starting to
re-surface. A considerable amount of recent work shows that this metabolic
disorder could be the source of cancer development (3, 18).
Interest in the Warburg effect waned considerably for a long period of
time. Part of the reason was the fact that Warburg was convinced that the
altered glucose metabolism in cancer cells was itself actually the cause of
cancer and that the most likely explanation for his observation was damage to
the mitochondria (11). Since then, modern molecular biology has
demonstrated that cancer cannot originate without a change to a cell’s
genome and that, at least in most cases; damage to the mitochondria is not
the explanation for why many cancer cells adopt aerobic glycolysis as the
principal pathway for glucose metabolism. However, during the past 15 years,
there has been a considerable increase in interest regarding the Warburg
effect and its role in cancer (7, 19-21).
There is considerable logic in targeting metabolic changes as an
approach to the development of pharmaceutical agents to treat cancer. It has
been hypothesized that this widespread prevalence is because aerobic
glycolysis provides a competitive advantage to cancer cells, allowing the
synthesis of compounds required for proliferation (3, 16).
A number of specific inhibitors of key enzymes involved in the aerobic
glycolytic pathway have been evaluated as potential anticancer drugs (3, 22).
However, few compounds have been used clinically, with a relative lack of
success (22). This suggests that a single inhibitor of cancer cell metabolism
might be insufficient to significantly inhibit cancer proliferation. Given the
extreme plasticity of malignant tissue, it seemed logical to attempt to use at
least two different compounds, each one targeted to interact with enzymes
catalyzing different steps.
α-LA and HCA are products that in combination have strong
antiproliferative effects against cancer cells, both in vitro and in vivo, by
targeting the cell metabolism.
The biological rationale for the use of this combination comes from the
fact that α-LA and HCA target two major enzymes of the metabolism of
glucose, namely pyruvate dehydrogenase (PDH) kinase (PDK) for α-LA and
ATP citrate lyase (ACL) for HCA. As described before, the Warburg effect
results in the conversion of glucose into pyruvate and then into lactate, even
in the presence of oxygen. By inhibiting PDK, α-LA will increase the activity of
PDH, resulting in the intra-mitochondrial use of pyruvate into the Krebs cycle
over cytoplasmic conversion of pyruvate into lactate. HCA inhibits ATP ACL,
limiting the conversion of cytoplasmic citrate into acetyl-CoA available for lipid
synthesis. Effects of α-LA and HCA would allow metabolic reprogramming of
cancer cells into metabolism based on oxidative phosphorylation. This
metabolic reprogramming would ultimately limit the availability of compounds
required for proliferation (3, 16).
α-LA is a drug approved in several countries (including Austria and
Germany) for the treatment of diabetic polyneuropathy. It is also sold over the
counter as an antioxidant. The treatment protocol for diabetic polyneuropathy
is 600 mg per day i.v. for two to four weeks followed by 600 mg per day of the
oral form, with no indication of the duration of the maintenance treatment.
Higher doses have been used in clinical trials for diabetic polyneuropathy.
Mcilduff and Rutkove reviewed five randomized clinical trials up to April 2011
for this indication (23). Two studies used the i.v. route alone and one study
used both i.v. and oral routes. Based on these results, 600 mg per day i.v. for
three weeks appears to be safe, with no more side-effects than with placebo,
while 600 mg twice per day i.v. for three weeks was responsible for more side-
effects than the placebo, but all were minor and reversible.
Another study on diabetic patients, this time to improve vascular
endothelial function, used 600 mg i.v. per day for three weeks and authors
reported “no adverse events or side-effects were detected in our study” (24).
Other groups have reported daily i.v. administration of 600 mg of α-LA for two
to three weeks in pre-diabetic or diabetic patients, with no mention of serious
adverse events (25-28), except for one patient who experienced chest
distress, which resolved after lowering the velocity of administration (26).
In patients with cancer, two groups reported the use of i.v. α-LA with
no serious adverse effects. In Austria, Gedlicka used i.v. α-LA to treat
polyneuropathy in 14 patients who experienced symptoms due to treatment
with docetaxel and cisplatin (28). Symptoms of polyneuropathy improved
rapidly with 600 mg i.v. once a week for 3-5 weeks followed by 1800 mg orally
twice daily until full recovery or for a maximum of six months. Apart from
moderate gastric pain in two patients and WHO grade 1 and 2 nausea in one
patient each, i.v. α-LA did not cause any other adverse reactions.
Hydroxycitrate is sold over the counter for weight loss, although its
efficacy for this purpose was not demonstrated in a well-conducted clinical
trial (29). In that trial, 1500 mg of HCA were administered daily for 12 weeks.
No patient was removed from the trial due to side-effects and no difference
was observed in the type and frequency of side-effects between the HCA and
the placebo groups.
According to Soni and al., a total of 15 clinical studies involving
approximately 914 subjects examining the effects of HCA have appeared in
the literature (30). Except for two studies, the dosages of HCA ranged from
900 to 2800 mg/day. In 14 placebo-controlled, double blind trials and one
single arm, open trial, employing up to 2800 mg/day HCA, no treatment-
related adverse effects were reported.
Naltrexone is a drug approved for the treatment of opioid intoxication,
and opioid and alcohol dependence. The interest of using low-dose naltrexone
together with α-LA and HCA to treat patients with cancer comes from several
In the early 1980s, Zagon and McLaughlin reported an
antiproliferative effect of naltrexone at low dose but not at standard dose (31).
This was later confirmed by several groups and in several models (32-44).
The exact mechanism of actions of this antiproliferative effect has not yet
been elucidated. A role for the inhibition of the opioid growth factor receptor
was suggested by Zagon and McLaughlin (31). The literature also suggests
that naltrexone may be an antagonist of toll-like receptor 4 (28). There is also
evidence that naltrexone has an effect on the insulin growth factor pathway,
which could also explain its antiproliferative effect. Naltrexone has been
shown to be able to reverse insulin resistance and to reduce insulin-like
growth factor I levels in patients (38–40). The insulin growth factor system is
well known to play a role in tumor initiation and progression (41) and is the
object of great interest in cancer research (42). Interest is even stronger for
two of its downstream pathways, Phosphoinositide 3-kinase/Protein kinase
B/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) signaling and Mitogen
Activated Protein/Extracellular signal-regulated kinase (MAP/ERK) pathway
(41-43). Therefore, it is hypothesized that naltrexone could have an effect on
the insulin growth factor system and downstream pathways, contributing to
the metabolic reprogramming of cancer cells.
Low-dose naltrexone has been used in adults at the dose of 0.5 mg to
4.5 mg in several clinical trials for multiple sclerosis, fibromyalgia, Crohn’s
disease, irritable bowel syndrome, systemic sclerosis and complex regional
pain syndrome (45-50). All side-effects reported were minor and the most
frequent ones were vivid dreams (not usually reported as unpleasant),
headaches and transient insomnia during a few days after initiation of the
treatment. Other less frequent side-effects were stomatitis, atopic dermatitis,
nausea, epigastric pain, mood alteration and joint pain. No grade III or IV side-
effects and no serious adverse events were related to the study medication.
There is preliminary data reporting concomitant use of α-LA and low-
dose naltrexone (4.5 mg per day at bedtime) in patients with advanced cancer
appears to be safe and has shown signs of efficacy in patients with advanced
diseases reported by Berkson and al. (12,13). Berkson and al. described five
case reports indicating possible efficacy in several cancer types. They
reported using α-LA together with low-dose naltrexone in many patients with
cancer. This series of patients is under evaluation by the best-case series
methodology implemented by the US National Cancer Institute (NCI).
Our preliminary work strongly suggests the lack of major toxicity of
metabolic treatment. The dose-limiting toxicity appears to be nausea and
vomiting. Three patients tried to increase the dose of α-LA to 1.2 g but
complained of severe nausea. No attempt to increase the dose of HCA was
To our knowledge, this is the first attempt to treat cancer using a
combination of molecules targeting abnormal cancer metabolism.
None of these patients experienced major side-effects of metabolic
At this stage of development, not a single case proves the efficacy of
treatment. But most patients are alive and well several months after having
sent home to die. Several months of life without symptoms strongly suggests
that targeting cancer metabolism may be a reasonable option in advanced
These results are in line with the previously published animal data
The role of metabolic treatment and its association with existing
therapy remains to be explored in well-conducted trials.
Laurent Schwartz patented the combination of lipoic acid and hydroxycitrate.
The other Authors have no competing interests. The Authors acknowledge the
help of Mireille Summa.
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Table 1: Summary of the medical characteristics of the patients reported in the
Patient Site of primary Number of
1 Lung 3 9 Months’ stabilization
2 Lung 2 Death
3 Colon 3 Stable disease
4 Colon 2 Death
5 Ovarian 3 Slow progression
6 Esophagus 2 Partial regression with
7 Uterine sarcoma 1 Stabilization
8 Liver 2 Partial stabilization
9 Unknown 2 Partial stabilization and
then progression
10 Parotid 2 Stable disease
11 Prostate 2 Regression
Figure 1. Chest CT of the first patient. Repeated CT demonstrated stable
Figure 2. Response of the liver metastases of an adenocarcinoma of the
esophagus to combined metabolic therapy and chemotherapy
Figure 3. Response to metabolic treatment of a metastatic
cholangiocarcinoma to the lung
Figure 4. Dramatic decrease of PSA following metabolic treatment
... 5-FU significantly decreased cancer cell growth in all three cell lines in a concentration-dependent manner, and MNTX enhanced the 5-FU effect. MNTX alone also showed antiproliferative activity although it did not [60]. ...
... Ten patients with metastatic renal cancer were treated with an IL-2 and NTX combination, and the majority showed decreased disease progression [53]. The second cases series report reported on a partial benefit in disease progression showed by a combined ALA and NTX treatment [60]. ...
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Purpose of Review Antagonists of mu-opioid receptor role in cancer progression remains to be elucidated. The objective of this review was to summarize the available evidence on antagonists of mu-opioid receptor effect on tumor progression and prognosis in different types of cancers and an evaluation of the available findings on their mechanism of action. Recent Findings We have found studies related to methylnaltrexone (MNTX) and naltrexone (NTX) usage in cancer outcomes-related setting. We found consistent preclinical evidence of a potential action of MNTX and NTX on cancer growth and spread mediated mainly by effect on the opioid growth factor receptor (OGFr) axis, which results in depressed cell replication. However, clinical results are scarce and limited to poor-quality evidence. Summary Further high-quality studies are warranted to study antagonists of mu-opioid receptor role as a therapeutic option in different types of cancer, especially in patients where the classical treatment causes unacceptable side effects.
... Moreover, in this line, our group has proposed new pH-dependent avenues for the treatment of human malignancies, ranging from brain tumors [29] to breast cancer [51,52] to other malignancies [28,30]. During the last few years, other groups have also activated clinical efforts to exploit the significantly diseased pH-related metabolic aspects of malignant tumors in cancer treatment [70,71]. ...
... Moreover, in this line, our group has proposed new pH-dependent avenues for the treatment of human malignancies, ranging from brain tumors [29] to breast cancer [51,52] to other malignant malignancies [28,30]. During the last few years, other groups have also activated clinical efforts to exploit the significantly diseased pH-related metabolic aspects of malignant tumors in cancer treatment [70,71]. ...
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Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “the Warburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H+), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO2 led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate…”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new “pH-related paradigm of cancer”, while at the same time addressing the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications.
... A group reported eleven cases from France [16] and all patients had failed standard chemotherapy and were offered only palliative care by their oncologists. Karnofsky status was between 50 and 60 with a life expectancy between two and six months. ...
... Therefore, restoration of mitochondrial biology in a way that activates the Krebs' cycle and manage apoptotic machinery might result in a breakthrough in the field of cancer medicine. One of those approach is that Schwartz et al., suggested the usage of metabolic treatment (Hydroxycitrate + α-Lipoic Acid) will restore the mitochondrial function 8,33,34 . Parallel of the context, the current work shows that FWGE has comparable pharmacological effect. ...
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Mitochondrial dysfunction and significant changes in metabolic pathways accompany cancer development and are responsible for maintaining the tumor microenvironment. Normal mitochondria can trigger intrinsic apoptosis by releasing cytochrome c into the cytosol. The survival of malignant cells highly depends on the suppression of this function. We validated that A250, a highly purified fraction of fermented wheat germ extract (FWGE), increases the carbon flux into the mitochondria, the expression of key elements of the Krebs cycle and oxidative phosphorylation (OXPHOS). The increased respiratory chain activity is related to the mitochondria’s ability to release cytochrome c into the cytosol, which triggers the apoptotic cascade. The 68% tumor growth inhibitory effect observed in the murine melanoma study is related to this effect, as proteomic analysis validated similar changes in mitochondrial protein levels in the isolated tumor tissue samples. Blood count data indicated that this effect was not accompanied by general toxicity. This study is significant, as it shows that a highly concentrated form of FWGE is an effective agent that increases normal mitochondrial functionality. The lack of hepatotoxic and general toxic effects makes A250 an excellent candidate targeting mitochondria function in cancer therapy.
Methionine enkephalin (MENK) has an important role in both neuroendocrine and immune systems. MENK was known as an opioid growth factor (OGF) for its growth regulatory characteristics. OGF interacts with the OGF receptor (OGFr) to inhibit DNA synthesis by upregulating p16 and/or p21, which delays the cell cycle transition from G0/G1 to S phase, and inhibits cell proliferation. In addition, OGF combines with OGFr in immune cells to exert its immunomodulatory activity and regulate immune function. OGF has been studied as an immunomodulator in a variety of autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, diabetes and viral infections, and has been proven to relieve symptoms of certain diseases in animal and in vitro experiments. Also, OGF and OGFr have various anti-tumor molecular mechanisms. OGF can be used as the primary therapy alone or combined with other drugs to treat tumors. This article summarizes the research progress of OGF in immune-related diseases and cancer diseases.
Naltrexone (NTX) is a nonspecific opioid antagonist that exerts pharmacological effects on the opioid axis by blocking opioid receptors distributed in cytoplastic and nuclear regions. NTX has been used in opioid use disorder (OUD), immune-associated diseases, alcoholism, obesity, and chronic pain for decades. However, low-dose naltrexone (LDN) also exhibits remarkable inhibition of DNA synthesis, viability, and other functions in numerous cancers and is involved in immune remodeling against tumor invasion and chemical toxicity. The potential anticancer activity of LDN is a focus of basic research. Herein, we summarize the associated studies on LDN oncotherapy to highlight the potential mechanisms and prospective clinical applications.
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Metabolic alterations associated with inflammation include increased recruitment of glycolysis (lactate release) and repression of mitochondrial oxidative phosphorylation. Inflammation causes hyperosmolar conditions in the extracellular medium. This thesis examines the consequences of hyperosmolarity on cellular bioenergetics. For this purpose we measured the cellular oxygen consumption rate (OCR) and proton production rate (PPR) for lactate release in the external medium. Two methodologies were used the high-resolution respirometer (O2k Oroboros Instruments) for OCR and the extracellular flux analyzer (Seahorse, Agilent) for OCR and PPR. The exposure cells to hypertonic conditions (600 milliOsmoles while normal value is 300) causes within few minutes a decrease in OCR (cellular respiration) that lasts for hours (indefinitely) and in the long term impact on cellular viability. This effect was observed with four different cell lines CHO (ovarian epithelial), HT29 (colonocytes), HEK293 (Embryonic kidney) and SH-SY5Y (Neuroblastoma). It was shown to be caused by three different osmolytes: Mannitol, polyethylene glycol, sodium chloride. A milder osmotic challenge (450 mOsm) caused a similar initial decrease but with restoration of initial OCR within few hours. The mechanisms underlying this effect have been investigated, hyperosmolarity impacts on mitochondrial respiration at different steps. A first effect is the inhibition of the mitochondrial ATP production step. In presence of glucose this is accompanied by a large increase in glycolysis (lactate release) that causes further mitochondrial inhibition by a second mechanism, which is likely to represent an enhancement of the Crabtree effect (inhibition of respiration by glycolysis) that impacts on respiratory complexes. In absence of glucose the cellular ATP turnover is seriously repressed surprisingly cellular survival is rather improved. These results raise therefore the question of the possible contribution of the hyperosmotic conditions caused by inflammation in the acquisition of the inflammatory metabolic profile.
Garcinia cambogia, with its active component hydroxycitric acid (HCA), is widely used for weight loss due to its anorexigenic effect, increased fat oxidation, and regulation of endogenous lipid biosynthesis. The potential effectiveness of G. cambogia in reducing body weight and fat has been concluded in several studies in both experimental animals and humans. However, the results of some randomized placebo-controlled human clinical trials have either not reported the same outcome or there has been a marginal reduction in body weight on a short-term basis, not beyond 12 weeks. Other beneficial effects of Garcinia in experimental studies include antiinflammatory, antiulcerogenic, antioxidant, hepatoprotective, cytotoxic, erythropoietic, and miscellaneous other effects. Studies with G. cambogia conducted in experimental animals have not reported mortality or significant toxicity. Further, at doses usually recommended for humans no side effects have been reported. However, G. cambogia should not be concurrently used with other drugs to circumvent drug interactions. Currently, a large number of G. cambogia/HCA-containing dietary supplements are being marketed, although the reports of toxicity associated with the regular use of these supplements have raised concerns. In most cases complaints have been related to formulations containing multiple ingredients including G. cambogia. Another reason for adverse effects of G. cambogia/HCA can be related to idiosyncratic reactions by individual patients or other drugs used concurrently with these supplements resulting into in a drug/herb-induced toxic interaction.
Background Naltrexone (NTX) is an opioid antagonist traditionally used as a treatment for alcohol and opioid use disorders, but various studies have documented its involvement in cancer progression, exploring possible anticancer potential, when administered at high doses or as low dose naltrexone (LDN). Herein we present a systematic review of cancer-related outcomes from case reports, clinical trials, and retrospective and prospective studies conducted using cell cultures, animal models, and human subjects receiving NTX/LDN.MethodsA systematic search of NTX in cancer therapy was conducted. Outcomes including tumor size and number, latency to tumor development, survival duration, progression of disease, and scan results were assessed in clinical and animal studies, and cell number was used as the outcome measure of culture studies.ResultsSeveral case reports demonstrate notable survival durations and metastatic resolutions in patients with late stage cancer when administered an average LDN dose of 3–5 mg/day. Animal and cell culture studies suggest an overarching principle of NTX involvement in cancer pharmacophysiology, suggesting that high doses and continuous administration can foster cancer progression, whereas low doses and intermittent treatment may hinder cell proliferation, impede tumorigenesis, and have potential anticancer efficacy.Conclusion This review emphasizes the value of potential future research on NTX in cancer therapy, and warrants need for a better understanding of underlying mechanisms. Future controlled studies with more robust sample sizes, particularly in humans, are needed to fully elucidate its potential in cancer therapy.
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The metabolism of tumor cells plays an important role in cancer development. Although aerobic glycolysis is inefficient from the standpoint of ATP production, it provides cancer cells with biomolecules implicated in the synthesis of lipids and nucleotides required for cellu-lar proliferation. Thus, targeting aerobic glycolysis has clearly been recognized as a poten-tially fruitful approach for the treatment of cancer. The inhibition of aerobic glycolysis by a combination of alpha lipoic acid and hydroxycitrate (METABLOC) is efficient to inhibit tu-mor development in several mouse models. In association with chemotherapy, it seems to im-prove survival of patients with tumors difficult to treat when compared to a single chemo-therapy regimen. We herein report our preliminary cases on both the clinical efficacy and side effects of METABLOC. Eleven patients with advanced metastatic cancer from were treated with per os 0.4 to 1.8 g of lipoic acid and 1.2 to 3 g of hydroxycitrate during 2 to 21 months inaddition to their normal chemotherapeutic regimen. Side effects occurred in half of the patients but were mild (grade 1-3) and limited to gastrointestinal disorders that disap-peared on using proton pump inhibitors or decreasing the doses. Five patients were charac-terized by a partial regression, 3 by a stable disease, and 3 by disease progression. In conclu-sion the results from these preliminary treatments support that METABLOC can be used safely with various common standard chemotherapeutic regimens. It also suggests that its use may slow down tumor growth, an observation that needs to be confirmed by a randomized controlled trial. Key words: cancer metabolism, antioxidants, hydroxycitrate (HCA), alpha-lipoic acid (ALA), glycolysis, METABLOC™, toxicity and clinical side effects of HCA and ALA.
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Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome, which involves glial activation and central sensitization in the central nervous system. Here, we describe positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone (a glial attenuator), in combination with other CRPS therapies. Prominent CRPS symptoms remitted in these two patients, including dystonic spasms and fixed dystonia (respectively), following treatment with low-dose naltrexone (LDN). LDN, which is known to antagonize the Toll-like Receptor 4 pathway and attenuate activated microglia, was utilized in these patients after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.
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To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue. Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain. When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported. The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.
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The most common of the neuropathies associated with diabetes mellitus, diabetic sensorimotor polyneuropathy (DSPN) is a syndrome of diffuse, length-dependent, symmetric nerve dysfunction. The condition is linked with substantial morbidity, frequent healthcare utilization, and compromised quality of life due to related discomfort. Correspondingly, antidepressants, anticonvulsants, and opioids are regularly prescribed with the goal of pain control. However, the agents rarely provide complete pain relief and fail to address progression of the disorder. Whereas strict blood glucose control can slow the onset and worsening of DSPN, near-normoglycemia is not easily attainable. Evidence implicating oxidative processes in the pathogenesis of DSPN offers one potentially important therapeutic avenue. Due to its properties as a potent antioxidant, alpha lipoic acid (ALA) could mitigate the development of DSPN and attenuate resultant symptoms and signs. Approved for treatment of DSPN in Germany, the agent is not more widely used due to uncertainty about its efficacy and reported adverse effects. Here we review the effectiveness and tolerability of ALA in the treatment of symptomatic DSPN. The MEDLINE, EMBASE, and Cochrane Library databases were searched for English-language literature on the topic. Randomized, blinded studies comparing parenteral and oral ALA with placebo in the treatment of peripheral neuropathy in diabetic adults were selected. Analysis included studies with a level of evidence of at least 2b. The current appraisal summarizes data from 1160 participants in the ALADIN, SYDNEY, ORPIL, SYDNEY 2, and ALADIN III trials. In four of the studies, ALA provided significant improvement in manifestations of DSPN. Treatment with ALA 600 mg iv daily for 3 weeks represents a well-tolerated and effective therapy for DSPN. An oral dose of 600 mg daily administered for up to 5 weeks could offer benefits in symptoms and signs of DSPN without significant side effects.
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Pruritus is a common symptom in systemic sclerosis (SSc), an autoimmune disease which causes fibrosis and vasculopathy in skin, lung, and gastrointestinal tract (GIT). Unfortunately, pruritus has limited treatment options in this disease. Pilot trials of low-dose naltrexone hydrochloride (LDN) for pruritus, pain, and quality of life (QOL) in other GIT diseases have been successful. In this case series we report three patients that had significant improvement in pruritus and total GIT symptoms as measured by the 10-point faces scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) questionnaire. This small case series suggests LDN may be an effective, highly tolerable, and inexpensive treatment for pruritus and GIT symptoms in SSc.
Endogenous opiates may affect various aspects of reproductive and metabolic function in patients with polycystic ovary syndrome (PCOS). This study evaluated long-term inhibition of the opioid system using naltrexone in clomiphene citrate (CC)-resistant women with PCOS. A group of 30 infertile females with PCOS were evaluated; all subjects were obese, hyperandrogenic and hyperinsulinemic; 16 patients were amenorrhic and 14 were oligomenorrhic. All subjects received natrexone (50 mg p.o. daily) for 6 months. Patients who did not ovulate after 12 weeks of naltrexone monotherapy, also received CC (starting at 50 mg/day for 5 days and, for non-responders, increasing it up to 150 mg/day). Of the 30 women, 3 ovulated during naltrexone monotherapy and 19 of the remaining 27 ovulated during naltrexone + CC therapy. There were no conceptions during naltrexone monotherapy, but 9 of 27 women (33.3%) conceived during naltrexone + CC; there was one missed abortion at 9 weeks, one preterm delivery at 34 weeks and seven term live births. Naltrexone therapy was also followed by significant reductions in BMI, fasting serum insulin, luteinizing hormone (LH), LH/follicle-stimulating hormone ratio and testosterone. In this preliminary trial, naltrexone improved endocrine and metabolic function in women with CC-resistant PCOS. Furthermore, naltrexone restored CC sensitivity in the majority of subjects, resulting in a significant number of pregnancies.
The opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin, is an endogenous opioid peptide that interacts with the OGF receptor (OGFr) to delay the G(1)/S interface of the cell cycle by modulating cyclin-dependent inhibitory kinase (CKI) pathways. The OGF-OGFr axis is a tonically active, inhibitory pathway that is an important regulator during homeostasis and re-epithelialization, and plays a role in the onset and progression of autoimmune diseases and cancer. Modulation of the OGF-OGFr axis can be accomplished by a variety of pharmacological and molecular approaches including use of intermittent or continuous exposure to the opioid antagonist naltrexone, genetic manipulation of OGFr expression, and antibody neutralization of OGF. Clinically, OGF is a biological therapy that has potential application for treatment of cancer. Currently, naltrexone at low dosages is being evaluated for treatment of autoimmune diseases such as Crohn's and multiple sclerosis. High dosages of naltrexone are effective in reversing dry eye and accelerating the repair of corneal abrasions in normal and diabetic rats; these studies are under investigation in the clinical setting. Naltrexone also enhances full-thickness wound closure in animal models of Type 1 or Type 2 diabetes, and translation of this knowledge to the clinic is planned. In summary, understanding the OGF-OGFr axis as a homeostatic regulator of proliferation has substantial implications for maintaining human health and treatment of disease.
Constructing metabolic profiles of 60 cancer cell lines by integrating metabolomics and systems biology revealed increased glycine consumption in highly proliferative cancer cells.
As a result of a spectrum of mitochondrial defects, tumor cells often preferentially use glycolysis to generate adenosine triphosphate (ATP), even in the presence of oxygen, a phenomenon known as aerobic glycolysis, or the "Warburg effect." Dichloroacetate (DCA) is an inhibitor of mitochondrial pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), a gatekeeping enzyme for the entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle. In mice, DCA treatment appears to reactivate mitochondrial respiration in tumor cells, induces their selective killing, and suppresses cancer growth. These observations provide intriguing insights into the plasticity of tumor metabolism that may offer new opportunities for therapeutic intervention.
Ovarian cancer is the leading cause of death from gynecological malignancies. Although initial therapeutic modalities are successful, 65% of these women relapse with only palliative treatments available thereafter. Endogenous opioids repress the proliferation of human ovarian cancer cells in vitro, and do so in a receptor-mediated manner. The present study examined whether modulation of opioid systems by the opioid antagonist naltrexone (NTX), alone or in combination with standard of care therapies (taxol/paclitaxel, cisplatin), alters human ovarian cancer cell proliferation in tissue culture and tumor progression in mice. Administration of NTX for six hours every two days, but not continuously, reduced DNA synthesis and cell replication from vehicle-treated controls in tissue culture. Moreover, brief exposure to NTX in combination with taxol or cisplatin had an enhanced anticancer action. Mice with established ovarian tumors and treated with a low dosage of NTX (LDN), which invokes a short period of opioid receptor blockade, repressed tumor progression in a non-toxic fashion by reducing DNA synthesis and angiogenesis but not altering cell survival. The combination of LDN with cisplatin, but not taxol, resulted in an additive inhibitory effect on tumorigenesis with enhanced depression of DNA synthesis and angiogenesis. LDN combined with cisplatin alleviated the toxicity (e.g. weight loss) associated with cisplatin. LDN treatment upregulated the expression of the opioid growth factor (OGF, chemical term ([Met(5)]-enkephalin) and its receptor, OGFr. Previous tissue culture studies have reported that OGF is the only opioid peptide with antiproliferative activity on ovarian cancer cells, with OGF action mediated by OGFr. Thus, the common denominator of intermittent opioid receptor blockade by short-term NTX or LDN on ovarian cancer proliferation and tumorigenesis recorded herein appears to be related to the OGF-OGFr axis. These preclinical data may offer a non-toxic and efficacious pathway-related treatment that can benefit patients with ovarian cancer.