title: The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells.
abstract: One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemo-resistant tumors. The aim of this study is to evaluate the role of Palomid 529 (P529), a novel TORC1/TORC2 inhibitor, in association with docetaxel (DTX) and cisplatin (CP). This work utilizes a wide panel of prostatic cancer cell lines with or without basal activation of Akt as well as two in vivo models of aggressive HRPC. The blockade of Akt/mTOR activity was associated to reduced cell proliferation and induction of apoptosis. Comparison of IC50 values calculated for PTEN-positive and PTEN-negative cell lines as well as the PTEN transfection in PC3 cells or PTEN silencing in DU145 cells revealed that absence of PTEN was indicative for a better activity of the drug. In addition, P529 synergized with DTX and CP. The strongest synergism was achieved when prostate cancer (PCa) cells were sequentially exposed to CP or DTX followed by treatment with P529. Treatment with P529 before the exposure to chemotherapeutic drugs resulted in a moderate synergism, whereas intermediated values of combination index were found when drugs were administered simultaneously. In vivo treatment of a combination of P529 with DTX or CP increased the percentage of complete responses and reduced the number of mice with tumor progression. Our results provide a rationale for combinatorial treatment using conventional chemotherapy and a Akt/mTOR inhibitor as promising therapeutic approach for the treatment of HRPC, a disease largely resistant to conventional therapies.
authors.affiliation: Laboratory of Radiobiology Division of Radiotherapy Oncology Endocrinology, Department of Experimental Medicine, University of L'Aquila, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.forename: Francesco
authors.initials: F
authors.lastname: Marampon
authors.forename: Foteini
authors.initials: F
authors.lastname: Petini
authors.forename: Leda
authors.initials: L
authors.lastname: Biordi
authors.forename: David
authors.initials: D
authors.lastname: Sherris
authors.forename: Emmanuele A
authors.initials: EA
authors.lastname: Jannini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tombolini
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D014157:Transcription Factors / Q000037:antagonists & inhibitors
chemical_list: D001578:Benzopyrans; C500984:CRTC1 protein, human; C493245:CRTC2 protein, human; D043823:Taxoids; D014157:Transcription Factors; D000077143:Docetaxel; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D002945:Cisplatin; C533469:palomid 529