title: 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 castration resistant prostate cancer (CRPC) is a foremost cause of men cancer death around the world. The aim of this work was to investigate 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: semisynthetic flavonoid that inhibits cyclin dependent kinases). We assessed CPS49-flavo or -PTX combinations cytotoxicity in a panel of PCa cell lines and PC3 xenografts. We found that CPS49 enhanced flavo or PTX cytotoxicity in human PCa cell lines while showed resistance in a non-tumor cell line. Furthermore, xenografts generated by inoculation of human prostate carcinoma PC3 cells in nu/nu mice showed that CPS49/flavo administration reduced tumor growth both after 2 weeks 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 of xenograft 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 combination showed that this treatment shut down the expression of several genes involved in adhesion, migration or invasion. In summary, the antitumor activity of CPS49 or flavopiridol was improved by the combination of these compounds and using half dose of that previously reported. Hence, CPS49-flavo combination is a promising new alternative for PCa therapy.
authors: Florencia
authors: F
authors: Zalazar
authors: Paola
authors: P
authors: De Luca
authors: Kevin
authors: K
authors: Gardner
authors: William D
authors: WD
authors: Figg
authors: Roberto
authors: R
authors: Meiss
authors: Raul G
authors: RG
authors: Spallanzani
authors: Pablo
authors: P
authors: Vallecorsa
authors: Belen
authors: B
authors: Elguero
authors: Javier
authors: J
authors: Cotignola
authors: Elba
authors: E
authors: Vazquez
authors: Laboratorio de Oncologia Molecular y Nuevos Blancos Terapeuticos (IBYME-CONICET), Vuelta de Obligado 2490, Buenos Aires, (C1428ADN), Argentina. adesiervi@qb.fcen.uba.ar.
authors: Adriana
authors: A
authors: De Siervi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005419:Flavonoids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C494622:CPS 49; D004338:Drug Combinations; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D013792:Thalidomide