CPS49 and Flavopiridol: a new selective drug combination for advanced prostate cancer.

ZALAZAR F; MOIOLA C; DE LUCA P; ELGUERO B; GARDNER K; FIGG WD; MEISS R; COTIGNOLA J; VAZQUEZ E; DE SIERVI A

Chicago

Congreso; Annual Meeting American Association for Cancer Research AACR; 2012

AACR

Prostate cancer (PCa) still ranks as the second most commonly diagnosedcancer and metastatic castration-resistant prostate cancer (CRPC) is aleading cause of cancer death in men around the world. The commontreatment for patients with CRPC is chemotherapy based on docetaxel.While there are currently seven agents approved for CRPC and fourregimens have shown some survival benefit, those survival prolongationshave 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 thatshow selective killing of leukemic cells by increasing intracellular reactiveoxygen species (ROS) and targeting multiple transcriptional pathways.Flavopiridol is a semisynthetic flavonoid that inhibits cyclin dependentkinases and also provokes lethality against leukemic cells. We previouslyfound that CPS49 and flavopiridol combination induced selective cytotoxicityassociated with mitochondrial dysfunction and elevations of ROS in leukemiccells ranging from additive to synergistic activity at low micromolarconcentrations. The goal of this study was to investigate the selectivity andefficacy of CPS49-flavopiridol combination in prostate cancer preclinicalmodels. Our results showed that flavopiridol enhanced CPS49 cytotoxicity inall human prostate tumor cell lines analyzed (PC3, C4-2, LNCaP and22RV1); however non tumor cell lines (293HEK and MCF10) were resistantto the tested doses. Furthermore, it was previously reported, high doses offlavopiridol (10 μM) or CPS49 (12 μM) were needed to inhibit tumor growthin PC3 xenograft mice compared with vehicle treated mice. Here, wedemonstrated that combining these two agents, antitumor activity wassynergistically enhanced with low doses. Injecting subcutaneously PC3 cellsin nu/nu mice, we found that CPS49-flavopiridol administration reducedtumor volume approximately 83% after 2 weeks of co-treatment and 54%after 1 week of low dose flavopiridol pretreatment and 2 weeks of drugcombination. In addition, we performed RT-qPCR array containing 26 genesfrom PC3 cells exposed to CPS49 and flavopiridol combination. Wedetermined that this treatment shut down the expression of several genesinvolved in cell cycle, DNA damage and tumor progression. Histologicalanalysis of xenograft PC3 tumor samples showed extensive areas ofnecrosis induced by the treatment.Furthermore, we assessed the efficacy of CPS49 in combination withpaclitaxel (docetaxel analog). All the prostate tumor cell lines tested werehighly sensitive to this combination. However, this combination did notreduce the tumor volume in PC3 xenografts. These results indicate that theCPS49 and flavopiridol is a promising new alternative for the treatment ofCRPC.