Novel CIL-102 derivatives as potential therapeutic agents for docetaxel-resistant prostate cancer

Dannah R. Miller, Cherng Chyi Tzeng, Trey Farmer, Evan T. Keller, Steve Caplan, Yu Shuin Chen, Yeh Long Chen, Ming Fong Lin

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

The standard-of-care treatment for metastatic prostate cancer (PCa) is androgen deprivation therapy (ADT). Nevertheless, most tumors eventually relapse and develop into lethal castration-resistant prostate cancer (CRPC). Docetaxel is a FDA-approved agent for the treatment of CRPC; however, the tumor often quickly develops resistance to this drug. Thus, there is an immediate need for novel therapies to treat docetaxel-resistant PCa. In this study, we modified the structure of CIL-102 and investigated the efficacy of the derivatives against CRPC and docetaxel-resistant PCa. These novel CIL-102 derivatives inhibit CRPC tumorigenicity, including proliferation, migration and colony formation, and importantly, selectively inhibit CRPC cell proliferation over non-cancerous prostate epithelia. Computational modeling indicated the derivatives bind to β-tubulin and immunocytochemistry revealed the depolymerization of microtubules upon treatment. Western blot analyses reveal that pro-apoptotic and anti-oxidant pathways are activated, and MitoSOX and DCF-DA analyses confirmed increased reactive oxygen species (ROS) production upon treatments. Furthermore, CIL-102 derivatives effectively reduce the proliferation of docetaxel-resistant CR PCa cell lines. Our data indicate the potential of these compounds as promising therapeutic agents for CRPC as well as docetaxel-resistant CRPC.

Original languageEnglish (US)
Pages (from-to)96-108
Number of pages13
JournalCancer Letters
Volume436
DOIs
StatePublished - Nov 1 2018

Keywords

  • Anti-microtubule agents
  • CIL-102 derivatives
  • CR PCa
  • Docetaxel-resistant cancer
  • Selectivity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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