TY - JOUR
T1 - Inhibition of Drug Resistance Mechanisms Improves the Benzyl Isothiocyanate–Induced Anti-Proliferation in Human Colorectal Cancer Cells
AU - Liu, Xiaoyang
AU - Yang, Qifu
AU - Nakamura, Yoshimasa
N1 - Funding Information:
This study was partly supported by MEXT KAKENHI Grant Numbers 17H03818 and 20H02933 (YN).
Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Autophagy
KW - Benzyl isothiocyanate
KW - Human colorectal cancer cells
KW - Nrf2
KW - Phosphoinositide 3-kinase
UR - http://www.scopus.com/inward/record.url?scp=85088927989&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088927989&partnerID=8YFLogxK
U2 - 10.1007/s40495-020-00227-4
DO - 10.1007/s40495-020-00227-4
M3 - Review article
AN - SCOPUS:85088927989
SN - 2198-641X
VL - 6
SP - 306
EP - 314
JO - Current Pharmacology Reports
JF - Current Pharmacology Reports
IS - 5
ER -