The Akt Inhibitor ISC-4 Activates Prostate Apoptosis Response Protein-4 and Reduces Colon Tumor Growth in a Nude Mouse Model

Department of Pharmacology, Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
Clinical Cancer Research (Impact Factor: 8.72). 06/2011; 17(13):4474-83. DOI: 10.1158/1078-0432.CCR-10-2370
Source: PubMed


Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy; however, Akt1 inactivates Par-4. Previously we showed that Par-4-overexpressing colon cancer cells responded more readily to 5-fluorouracil (5-FU) than their wild-type counterparts. In this study we investigated (i) the effects of the Akt inhibitor, phenylbutyl isoselenocyanate (ISC-4), on tumor growth in nude mice and (ii) bystander effect of Par-4-overexpressing cells on wild-type tumor growth.
Mice (n = 80) were injected with wild-type HT29 human colon cancer cells in the right flank. Forty of the mice were also injected in the left flank with HT29 cells engineered to overexpress Par-4. The mice were treated with 5-FU, ISC-4, a combination, or vehicle.
ISC-4 reduced tumor growth, with or without 5-FU. When Par-4-overexpressing tumors were present, wild-type tumors grew more slowly compared to when no Par-4-overexpressing tumors were present. The level of Par-4 protein as well as the Par-4 binding protein, GRP78, was increased in wild-type cells growing in the same mouse as Par-4-overexpressing tumors compared with wild-type tumors growing without Par-4-overexpressing tumors.
Par-4-overexpressing tumors exhibited a bystander effect on wild-type tumors growing distally in the same mouse. This suggests that gene therapy need not achieve total penetration to have a positive effect on tumor treatment. Inhibition of Akt with ISC-4 inhibited tumor growth and had a greater effect on cells overexpressing Par-4. The data indicate ISC-4 alone or in combination with Par-4 can greatly reduce tumor growth.

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    • "Among the investigated ISCs, ISC-4 has shown the best anti-tumor activity in preclinical models, both in vitro and in vivo, with promising safety [4]. ISC-4 has demonstrated modest preclinical efficacy against many tumor types in vitro, and anti-tumor effects have been reported in the context of melanoma when ISC-4 is used a mono-agent in vivo [4], [5], [6]. ISC-4 also has exhibited significant anti-tumor effects, via the inhibition of Akt, in colon cancer xenografts when used as a mono-agent and when used in combination with 5-fluorouracil (5-FU)—though the clinical utility of the combination was unclear [5]. "
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    ABSTRACT: Phenylbutyl isoselenocyanate (ISC-4) is an Akt inhibitor with demonstrated preclinical efficacy against melanoma and colon cancer. In this study, we sought to improve the clinical utility of ISC-4 by identifying a synergistic combination with FDA-approved anti-cancer therapies, a relevant and appropriate disease setting for testing, and biomarkers of response. We tested the activity of ISC-4 and 19 FDA-approved anticancer agents, alone or in combination, against the SW480 and RKO human colon cancer cell lines. A synergistic interaction with cetuximab was identified and validated in a panel of additional colon cancer cell lines, as well as the kinetics of synergy. ISC-4 in combination with cetuximab synergistically reduced the viability of human colon cancer cells with wild-type but not mutant KRAS genes. Further analysis revealed that the combination therapy cooperatively decreased cell cycle progression, increased caspase-dependent apoptosis, and decreased phospho-Akt in responsive tumor cells. The synergism between ISC-4 and cetuximab was retained independently of acquired resistance to 5-FU in human colon cancer cells. The combination demonstrated synergistic anti-tumor effects in vivo without toxicity and in the face of resistance to 5-FU. These results suggest that combining ISC-4 and cetuximab should be explored in patients with 5-FU-resistant colon cancer harboring wild-type KRAS.
    PLoS ONE 11/2013; 8(3):e59380. DOI:10.1371/journal.pone.0059380 · 3.23 Impact Factor
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    • "Recently,Burikhanovetal.(2009)demonstratedthat PAR-4isspontaneouslysecretedbynormalandcancercells incultureindependentlyofcaspaseactivationorapoptosis [25].Notably,extracellularPAR-4inducesapoptosisby bindingtothestressresponseproteinglucose-regulated protein-78(GRP78),whichisexpressedonthesurfaceof cancercells.TheinteractionofextracellularPAR-4andcell surfaceGRP78effectsapoptosisthroughERstressandacti- vationoftheFADD/caspase-8/caspase-3pathway.This pathwayisessentialforapoptosisbyTRAIL,which,like PAR-4,inducescancer-specificapoptosis. Sharmaetal.(2011)alsoobservedthatwild-typetumor growthwasimpairedduetothesecretionofPAR-4from distanttumors;theidentificationofanextracellularfunction ofPAR-4significantlyexpandsitstherapeuticpotentialfor primaryandmetastatictumors[26].Anotherrecentstudy providednovelevidencethatPAR-4isaphysiologicalsub- strateofcaspase-3andiscleavedduringapoptosisandthat PAR-4degradationfacilitatestheinductionofapoptosis[27]. "
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    ABSTRACT: PAR-4 is a tumor suppressor protein with a pro-apoptotic function and down-regulation of PAR-4 is seen in a variety of tumors. PHLDA1 gene overexpression has been shown to reduce cell proliferation and induce cell death in a variety of cell types. In this study, 229 cases of oral squamous cell carcinoma (OSCC), arranged in a tissue microarray, were analyzed by immunohistochemistry. PAR-4 expression was predominantly moderate to strong and expression of PHLDA1 was predominantly negative or weak. Cytoplasmic expression of PAR-4 was associated with advanced clinical stage. Expression of PHLDA1 was associated with advanced clinical stage of the tumour. Five-year overall and disease-free survival rates differed significantly between cases that did and cases that did not express PHLDA1, and by multivariate analysis, expression of PHLDA1 and PAR-4 were independent prognostic factors in OSCC patients. Expression of PAR-4 and PHLDA1 is altered in OSCC and might be a valuable prognostic indicator for this disease.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2013; 463(1). DOI:10.1007/s00428-013-1438-9 · 2.65 Impact Factor
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    • "Nguyen et al. [27] have reported a structurally related compound, 4-phenylbutylisoselenocyanate (ISC-4) (Figure 2) that decreased Akt3 signaling and led to a 3-fold increase in apoptosis rates. Later, in a nude mouse model injected with wild-type HT-29 colon cancer cells, ISC-4 was shown to inhibit tumor growth significantly via the inhibition of Akt, which was more pronounced in culture cells than others Akt inhibitors [28]. There have been other reports showing Se compounds with selenocyanate moiety to act as Akt modulators. "
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    ABSTRACT: Selenium (Se) is an essential trace element involved in different physiological functions of the human body and plays a role in cancer prevention and treatment. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. The mechanisms of Se-induced apoptosis are associated with the chemical forms of Se and their metabolism as well as the type of cancer studied. So, some selenocompounds, such as SeO(2) involve the activation of caspase-3 while sodium selenite induces apoptosis in the absence of the activation of caspases. Modulation of mitochondrial functions has been reported to play a key role in the regulation of apoptosis and also to be one of the targets of Se compounds. Other mechanisms for apoptosis induction are the modulation of glutathione and reactive oxygen species levels, which may function as intracellular messengers to regulate signaling pathways, or the regulation of kinase, among others. Emerging evidence indicates the overlaps between the apoptosis and other types of cell death such as autophagy. In this review we report different processes of cell death induced by Se compounds in cancer treatment and prevention.
    International Journal of Molecular Sciences 12/2012; 13(8):9649-72. DOI:10.3390/ijms13089649 · 2.86 Impact Factor
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