title: Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTOR pathway inhibition in a Pten defecient model of prostate cancer.
abstract: Increased expression of histone deacetylases (HDACs) and activation of the PI3K-Akt-mTORC1 pathway are common aberrations in prostate cancer (PCa). For this reason, inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa. Previous reports demonstrated that HDAC inhibitors (HDACi) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor (AR). In this study we utilized the AR negative PCa cell line and observed that re-expression of AR (PC3-AR) results in greater levels of apoptosis when treated with the pan-DACi, panobinostat (PAN). PAN mediated apoptosis in PC3 and PC3-AR cells was associated with increased levels of double strand DNA breaks, indicated by p-ɣH2AX. Further, PAN treatment in PC3-AR cells resulted in moderate attenuation of the ATM-Akt-ERK DNA damage response pathway. For this reason, we combined PAN with the dual PI3K-mTOR inhibitor, BEZ235. Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein ATM and significantly increased anti-tumor activity compared to each single treatment. Overall, superior anti-tumor activity with combination of PAN with BEZ235 was independent of AR status. These findings suggest that this therapeutic strategy should be further developed in clinical trials.
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo NY.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ellis
authors.forename: Sheng Yu
authors.initials: SY
authors.lastname: Ku
authors.forename: Swathi
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: Elena
authors.initials: E
authors.lastname: Lasorsa
authors.forename: Gizzou
authors.initials: G
authors.lastname: Azabdaftari
authors.forename: Alejandro
authors.initials: A
authors.lastname: Godoy
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000077767:Panobinostat; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007093:Imidazoles; D007211:Indoles; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D000077767:Panobinostat; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human; C531198:dactolisib