Inhibition of Drug Resistance Mechanisms Improves the Benzyl Isothiocyanate–Induced Anti-Proliferation in Human Colorectal Cancer Cells

Xiaoyang Liu, Qifu Yang, Yoshimasa Nakamura

Research output: Contribution to journalReview article

Abstract

Purpose of Review: This short review is aimed at summarizing our recent findings about the regulating role of PI3K in the benzyl isothiocyanate (BITC)–induced drug-resistant mechanisms in human colorectal cancer cells and identification of potential components to overcome this resistance by combinatory utilization. Recent Findings: Benzyl isothiocyanate (BITC), the organosulfur compounds derived from cruciferous vegetables, exerts anti-proliferative effects in various human cancer cells. BITC also enhances the activation of the phosphoinositide 3-kinase (PI3K)/Akt survival pathway, possibly through the inhibition of the protein tyrosine phosphatase 1B. Since the PI3K/Akt pathway as well as drug efflux mediates resistance against anti-cancer drugs, it is important to find an agent to improve the anti-cancer effects of BITC without enhancing the side effects. We have shown that inhibition of PI3K or depletion of the plasma membrane cholesterol significantly enhanced the BITC-induced apoptosis, coinciding with inhibition of the survival pathway. Furthermore, BITC induced autophagy concomitantly with the up-regulation of the nuclear factor–erythroid 2 (NF-E2)–related factor 2 (Nrf2) and Nrf2-dependent cytoprotective genes in human colorectal cancer cells. Experiments using PI3K inhibitors implicated that PI3K is involved not only in the accumulation of autophagic molecules but also the up-regulation of Nrf2 with p62/sequestosome-1. PI3K might play pivotal roles in the resistant mechanisms, such as the activation of cell survival signaling and autophagy-dependent drug metabolism in human colon cancer cells. Summary: Our studies suggest that combinatory treatment of PI3K inhibitors or cholesterol-depleting agents is a promising strategy to improve the BITC-induced anti-cancer effects in human colorectal cancer cells.

Original languageEnglish
Pages (from-to)306-314
Number of pages9
JournalCurrent Pharmacology Reports
Volume6
Issue number5
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • Apoptosis
  • Autophagy
  • Benzyl isothiocyanate
  • Human colorectal cancer cells
  • Nrf2
  • Phosphoinositide 3-kinase

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Pharmacology
  • Drug Discovery

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