Abstract 2340: CPS49 and Flavopiridol: a new selective drug combination for advanced prostate cancer
Authors: Zalazar Florencia , Luca Paola De , Elguero Belén , Gardner Kevin , Figg William D. , Meiss Roberto , Moiola Cristian P. , Cotignola Javier , Vazquez Elba S. , Siervi Adriana De 
Published: August 2012

Prostate cancer (PCa) still ranks as the second most commonly diagnosed cancer and metastatic castration-resistant prostate cancer (CRPC) is a leading cause of cancer death in men around the world. The common treatment for patients with CRPC is chemotherapy based on docetaxel. While there are currently seven agents approved for CRPC and four regimens have shown some survival benefit, those survival prolongations have been modest and unfortunately all patients will eventually progress. Thus, there is a need for new agents and regimens for this disease. 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin dependent kinases and also provokes lethality against leukemic cells. We previously found that CPS49 and flavopiridol combination induced selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. The goal of this study was to investigate the selectivity and efficacy of CPS49-flavopiridol combination in prostate cancer preclinical models. Our results showed that flavopiridol enhanced CPS49 cytotoxicity in all human prostate tumor cell lines analyzed (PC3, C4-2, LNCaP and 22RV1); however non tumor cell lines (293HEK and MCF10) were resistant to the tested doses. Furthermore, it was previously reported, high doses of flavopiridol (10 μM) or CPS49 (12 μM) were needed to inhibit tumor growth in PC3 xenograft mice compared with vehicle treated mice. Here, we demonstrated that combining these two agents, antitumor activity was synergistically enhanced with low doses. Injecting subcutaneously PC3 cells in nu/nu mice, we found that CPS49-flavopiridol administration reduced tumor volume approximately 83% after 2 weeks of co-treatment and 54% after 1 week of low dose flavopiridol pretreatment and 2 weeks of drug combination. In addition, we performed RT-qPCR array containing 26 genes from PC3 cells exposed to CPS49 and flavopiridol combination. We determined that this treatment shut down the expression of several genes involved in cell cycle, DNA damage and tumor progression. Histological analysis of xenograft PC3 tumor samples showed extensive areas of necrosis induced by the treatment. Furthermore, we assessed the efficacy of CPS49 in combination with paclitaxel (docetaxel analog). All the prostate tumor cell lines tested were highly sensitive to this combination. However, this combination did not reduce the tumor volume in PC3 xenografts. These results indicate that the CPS49 and flavopiridol is a promising new alternative for the treatment of CRPC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2340. doi:1538-7445.AM2012-2340