title: Combination therapy of paclitaxel and cyclopamine polymer-drug conjugates to treat advanced prostate cancer.
abstract: Repeated treatments with chemotherapeutic agent(s) fail due to cancer stem cells (CSCs) and chemoresistance regulated by microRNAs (miRNA) whose expression alters owing to dysfunctional signaling pathways including Hedgehog (Hh) signaling. We previously demonstrated the combination of Hh inhibitor cyclopamine (CYP) and paclitaxel (PTX) effectively inhibit PTX-resistant cells and side population, a cell fraction rich in CSCs. In this study, we synthesized mPEG-b-PCC-g-PTX-g-DC (P-PTX) and mPEG-b-PCC-g-CYP-g-DC (P-CYP) polymer-drug conjugates, which they self-assembled into micelles. The combination of P-PTX and P-CYP alleviated PTX resistance and suppressed tumor colony formation. Further, combination therapy inhibited Hh signaling and up-regulated tumor suppressor miRNAs. We established orthotopic prostate tumor in nude mice and there was significant tumor growth inhibition in the group treated with the combination therapy of P-PTX and P-CYP compared with monotherapy. In conclusion, this combination therapy of P-PTX and P-CYP has the potential to treat chemoresistant prostate cancer.
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE.
authors: Ruinan
authors: R
authors: Yang
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE.
authors: Goutam
authors: G
authors: Mondal
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE.
authors: Di
authors: D
authors: Wen
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE. Electronic address: ram.mahato@unmc.edu.
authors: Ram I
authors: RI
authors: Mahato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D058726:Nanoconjugates; D017239:Paclitaxel / Q000008:administration & dosage*; D011108:Polymers / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014704:Veratrum Alkaloids / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D058726:Nanoconjugates; D011108:Polymers; D014704:Veratrum Alkaloids; D017239:Paclitaxel; C000541:cyclopamine
keywords: Chemoresistance; Cyclopamine; Paclitaxel; Polymer-drug conjugate; Prostate cancer