Methyl-β-cyclodextrin potentiates the BITC-induced anti-cancer effect through modulation of the Akt phosphorylation in human colorectal cancer cells

Methyl-β-cyclodextrin (MβCD) is an effective agent for the removal of plasma membrane cholesterol. In this study, we investigated the modulating effects of MβCD on the antiproliferation induced by benzyl isothiocyanate (BITC), an ITC compound mainly derived from papaya seeds. We confirmed that MβCD...

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Bibliographic Details
Published in:Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2018-12, Vol.82 (12), p.2158-2167
Main Authors: Yang, Qifu, Miyagawa, Miku, Liu, Xiaoyang, Zhu, Beiwei, Munemasa, Shintaro, Nakamura, Toshiyuki, Murata, Yoshiyuki, Nakamura, Yoshimasa
Format: Article
Language:English
Subjects:
Akt
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacology
apoptosis
Apoptosis - drug effects
benzyl isothiocyanate
beta-Cyclodextrins - administration & dosage
beta-Cyclodextrins - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
cholesterol
Cholesterol - metabolism
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Culture Media
Dose-Response Relationship, Drug
Drug Synergism
Humans
Isothiocyanates - administration & dosage
Isothiocyanates - pharmacology
Methyl-β-cyclodextrin
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt - metabolism
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Summary:Methyl-β-cyclodextrin (MβCD) is an effective agent for the removal of plasma membrane cholesterol. In this study, we investigated the modulating effects of MβCD on the antiproliferation induced by benzyl isothiocyanate (BITC), an ITC compound mainly derived from papaya seeds. We confirmed that MβCD dose-dependently increased the cholesterol level in the medium, possibly through its removal from the plasma membrane of human colorectal cancer cells. The pretreatment with a non-toxic concentration (2.5 mM) of MβCD significantly enhanced the BITC-induced cytotoxicity and apoptosis induction, which was counteracted by the cholesterol supplementation. Although BITC activated the phosphoinositide 3-kinase (PI3K)/Akt pathway, MβCD dose-dependently inhibited the phosphorylation level of Akt. On the contrary, the treatment of MβCD enhanced the phosphorylation of mitogen activated protein kinases, but did not potentiate their BITC-induced phosphorylation. These results suggested that MβCD might potentiate the BITC-induced anti-cancer by cholesterol depletion and thus inhibition of the PI3K/Akt-dependent survival pathway. Abbreviations: CDs: cyclodextrins; MβCD: methyl-β-cyclodextrin; ITCs: isothiocyanates; BITC: benzyl isothiocyanate; PI3K: phosphoinositide 3-kinase; PDK1: phosphoinositide-dependent kinase-1; MAPK: mitogen activated protein kinase; ERK1/2: extracellular signal-regulated kinase1/2; JNK: c-Jun N-terminal kinase; PI: propidium iodide; FBS: fatal bovine serum; TLC: thin-layer chromatography; PBS(-): phosphate-buffered saline without calcium and magnesium; MEK: MAPK/ERK kinase; PIP2: phosphatidylinositol-4,5-bisphosphate; PIP3: phosphatidylinositol-3,4,5-trisphosphate MβCD potentiated the BITC-induced antiproliferation through inhibition of the PI3K/AKT survival pathway
ISSN:0916-8451
1347-6947
DOI:10.1080/09168451.2018.1514249