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

Authors:

Abstract

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: laurent.schwartz@polytechnique.edu
Key Words: Hydroxycitrate, alpha lipoic acid, low-dose naltrexone,
metabolism, advanced cancer.
1
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.
2
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
3
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).
4
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.
Patients
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
(n=1).
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.
Results
5
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.
6
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.
7
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
8
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
4.
Discussion
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
9
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
10
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
11
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
observations.
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
12
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
reported.
Conclusion
13
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
treatment.
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
disease.
These results are in line with the previously published animal data
(51).
The role of metabolic treatment and its association with existing
therapy remains to be explored in well-conducted trials.
Acknowledgements
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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19
Table 1: Summary of the medical characteristics of the patients reported in the
study
Patient Site of primary Number of
chemotherapy
lines
Evolution
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
chemotherapy
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
20
Figure 1. Chest CT of the first patient. Repeated CT demonstrated stable
disease
21
Figure 2. Response of the liver metastases of an adenocarcinoma of the
esophagus to combined metabolic therapy and chemotherapy
22
Figure 3. Response to metabolic treatment of a metastatic
cholangiocarcinoma to the lung
23
Figure 4. Dramatic decrease of PSA following metabolic treatment
24
... 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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... 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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... Methylene blue, a century-old drug, can receive an electron from NADH in the presence of complex I and donates it to cytochrome c, providing an alternative electron transfer pathway in defective mitochondria (Schwartz et al. 2013(Schwartz et al. , 2014Yang et al. 2017). In the AD, Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. ...
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... Although the aerobic glycolysis phenotype has been identified in cancer cells since the 1920's [33], it is only since 2011 that Otto Warburg's definition of deregulated cellular energetics was included as part of the "hallmarks of cancer" [34]. This novel approach led to studies on the metabolic therapy of cancer at pre-clinical and clinical levels, testing drugs known to modulate the activity of enzymes that can maximize mitochondrial fluxes [35][36][37][38][39]. In this work, metabolic similarities of CHOs with cancer cells guided the selection of potential drug candidates, among which α-lipoic acid (α-LA), acting at the glycolysis/TCA interface, and methylene blue (MB), enhancing respiratory pathways, were tested. ...
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The Warburg effect, a hallmark of cancer, has recently been identified as a metabolic limitation of Chinese Hamster Ovary (CHO) cells, the primary platform for the production of monoclonal antibodies (mAb). Metabolic engineering approaches, including genetic modifications and feeding strategies, have been attempted to impose the metabolic prevalence of respiration over aerobic glycolysis. Their main objective lies in decreasing lactate production while improving energy efficiency. Although yielding promising increases in productivity, such strategies require long development phases and alter entangled metabolic pathways which singular roles remain unclear. We propose to apply drugs used for the metabolic therapy of cancer to target the Warburg effect at different levels, on CHO cells. The use of α-lipoic acid, a pyruvate dehydrogenase activator, replenished the Krebs cycle through increased anaplerosis but resulted in mitochondrial saturation. The electron shuttle function of a second drug, methylene blue, enhanced the mitochondrial capacity. It pulled on anaplerotic pathways while reducing stress signals and resulted in a 24% increase of the maximum mAb production. Finally, the combination of both drugs proved to be promising for stimulating Krebs cycle activity and mitochondrial respiration. Therefore, drugs used in metabolic therapy are valuable candidates to understand and improve the metabolic limitations of CHO-based bioproduction.
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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.
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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.