Androgen-independent prostate cancer is associated with an extremely poor treatment response and a limited prognosis using current treatment modalities. Therefore, the development of new therapeutic strategies for advanced prostate cancer represents a goal with enormous clinical and scientific merit. Findings from our laboratory indicate that treatment of prostate cancer cells with the zinc chelating agent N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces selective down-regulation of the X-linked inhibitor of apoptosis protein (XIAP) and sensitizes cancer cells to death ligand-mediated apoptosis. We have also observed a significant reduction of XIAP levels in cells treated with protoporphyrin IX, a naturally occurring chelating molecule. Moreover, the intracellular accumulation of protoporphyrin IX, after exogenous administration of its precursor 5-ALA, coincides with reduced XIAP expression in PC-3 prostate cancer cells and an increased sensitivity to TRAIL-mediated apoptosis. The preferential accumulation of protoporphyrin IX and its derivatives in neoplastic lesions is well established and has been extensively employed for photodetection and photodynamic therapy in various malignancies. We hypothesize that displacement of zinc sensitizes malignant cells to cytotoxic agents via down-regulation of XIAP and, therefore, zinc chelation might represent a novel mechanism for prostate cancer therapy. Importantly, our data and the results of others demonstrate that the depletion of XIAP by itself is sufficient to reverse resistance to TRAIL-mediated apoptosis in cancer cells. To test our hypothesis and to evaluate the therapeutic uses of zinc chelating agents in prostate cancer, we propose the following Specific Aims:
Aim 1 : To identify 5-ALA derivatives with improved capability of sensitizing prostate cancer cells to cytotoxic agents in vitro;
Aim 2 : To examine the oral bioavailability of 5-ALA esterified derivatives and the tissue distribution of 5-ALA induced PPIX in a xenograft model of prostate cancer;
Aim 3 : To examine the in vivo anti-tumor efficacy and toxicity of 5-ALA derivatives. XIAP levels are elevated in many cancer cell lines, and suppression of XIAP protein levels can sensitize cancer cells to cytotoxic drugs. This makes XIAP an attractive target for the design of novel anti-tumor agents.

Public Health Relevance

Findings from our laboratory indicate that treatment of prostate cancer cells with the zinc chelating agents N, N, N', N', -tetrakis (2-pyridylmethyl) ethlenediamine (TPEN) and protoporphyrin IX induces down-regulation of the X-linked inhibitor of apoptosis protein (XIAP). Moreover, the intracellular accumulation of protoporphyrin IX after exogenous administration of its precursor, 5-aminolevulinic acid, coincides with reduced XIAP expression in PC-3 prostate cancer cells and an increased sensitivity to TRAIL-mediated apoptosis. We seek to evaluate the therapeutic uses of 5-ALA for the treatment of hormone refractory prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134463-04
Application #
8259183
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2009-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$323,055
Indirect Cost
$141,907
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Naito, Sei; Makhov, Peter; Astsaturov, Igor et al. (2017) LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma. Br J Cancer 116:1203-1207
Golovine, Konstantin; Makhov, Peter; Naito, Sei et al. (2015) Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma. Cancer Biol Ther 16:743-9
Makhov, P; Golovine, K; Teper, E et al. (2014) Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death. Br J Cancer 110:899-907
Ginzburg, Serge; Golovine, Konstantin V; Makhov, Petr B et al. (2014) Piperlongumine inhibits NF-?B activity and attenuates aggressive growth characteristics of prostate cancer cells. Prostate 74:177-86
Kolenko, Vladimir; Teper, Ervin; Kutikov, Alexander et al. (2013) Zinc and zinc transporters in prostate carcinogenesis. Nat Rev Urol 10:219-26
Golovine, Konstantin V; Makhov, Peter B; Teper, Ervin et al. (2013) Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells. Prostate 73:23-30
Makhov, Peter; Golovine, Konstantin; Canter, Daniel et al. (2012) Co-administration of piperine and docetaxel results in improved anti-tumor efficacy via inhibition of CYP3A4 activity. Prostate 72:661-7
Teper, Ervin; Makhov, Peter; Golovine, Konstantin et al. (2012) The effect of 5-aminolevulinic acid and its derivatives on protoporphyrin IX accumulation and apoptotic cell death in castrate-resistant prostate cancer cells. Urology 80:1391.e1-7
Makhov, Peter B; Golovine, Konstantin; Kutikov, Alexander et al. (2012) Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells. Mol Cancer Ther 11:1510-7
Kutikov, Alexander; Makhov, Peter; Golovine, Konstantin et al. (2011) Interleukin-6: a potential biomarker of resistance to multitargeted receptor tyrosine kinase inhibitors in castration-resistant prostate cancer. Urology 78:968.e7-11

Showing the most recent 10 out of 14 publications