Low doses of CPS49 and flavopiridol combination as potential treatment for advanced prostate cancer

Abstract

Prostate cancer (PCa) still ranks as the second most frequently diagnosed cancer and metastatic castrationresistantprostate cancer (CRPC) is a foremost cause of men cancer death around the world. The aim of this work was toinvestigate the selectivity and efficacy of new drug combinations for CRPC. We combined three compounds: paclitaxel(PTX: taxane that inhibits microtubule polymerization); 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49; redox-reactive thalidomide analog with anti-angiogenic properties) and flavopiridol (flavo: semisyntheticflavonoid that inhibits cyclin dependent kinases). We assessed CPS49-flavo or -PTX combinations cytotoxicityin a panel of PCa cell lines and PC3 xenografts. We found that CPS49 enhanced flavo or PTX cytotoxicity in human PCacell lines while showed resistance in a non-tumor cell line. Furthermore, xenografts generated by inoculation of humanprostate carcinoma PC3 cells in nu/nu mice showed that CPS49/flavo administration reduced tumor growth both after 2weeks of co-treatment and after 1 week of pretreatment with a low dose of flavo followed by 2 weeks of co-treatment.PTX and CPS49 combination did not significantly reduce tumor growth in PC3 xenografts. Histological analysis ofxenograft PC3 tumor samples from CPS49/flavo combination showed extensive areas of necrosis induced by the treatment.RT-qPCR array containing 23 genes from PC3 cells or PC3 xenografts exposed to CPS49/flavo combinationshowed that this treatment shut down the expression of several genes involved in adhesion, migration or invasion. Insummary, the antitumor activity of CPS49 or flavopiridol was improved by the combination of these compounds and usinghalf dose of that previously reported. Hence, CPS49-flavo combination is a promising new alternative for PCa therapy.