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

Abstract

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.

Synthetic Receptors for Early Detection and Treatment of Cancer

“…All of the mice treated with methylated cyclodextrin or doxorubicin died within 70 days, whilst all the mice treated with the folate-derivative survived for at least 140 days. In other work, the simpler methylated cyclodextrin was shown to remove cholesterol from plasma membranes, and, in conjunction with benzyl isothiocyanate, it demonstrated enhanced cytotoxicity against human colorectal cancer cells [80]. Similar effects could be obtained using methylated cyclodextrin along with the anticancer drug tamoxifen; the In other work, the simpler methylated cyclodextrin was shown to remove cholesterol from plasma membranes, and, in conjunction with benzyl isothiocyanate, it demonstrated enhanced cytotoxicity against human colorectal cancer cells [80].…”

Transcriptome Analysis and Weighted Gene Co-expression Network Reveal Multitarget-Directed Antibacterial Mechanisms of Benzyl Isothiocyanate against Staphylococcus aureus

“…This further supported its potential for the control and suppression of microbial pathogens in food. It has been reported that BITC can regulate the expression and function of apoptosis-related proteins through c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 signal transduction pathways, leading to tumor cell apoptosis . However, these pathways are conserved in eukaryotic cells, and it is hard to connect them to the bactericidal effects of BITC on S.…”

“…It has been reported that BITC can regulate the expression and function of apoptosis-related proteins through c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 signal transduction pathways, leading to tumor cell apoptosis. 21 However, these pathways are conserved in eukaryotic cells, and it is hard to connect them to the bactericidal effects of BITC on S. aureus cells. In most cases, the antibacterial activity of BITCs was attributed to its destructive roles in cell envelope integrity, involving Clostridium perfringens, S. aureus, etc.…”

Cruciferous vegetables as a treasure of functional foods bioactive compounds: Targeting p53 family in gastrointestinal tract and associated cancers

“…In addition, they increase apoptosis-related proteins due to activation of p53-family genes, while decreasing metastasis-related proteins. Because of all these reasons, BITC, PEITC and sulforaphane were capable of ameliorating the inflammation associated with colon cancer ( 116 , 167 ). In HT29 colon cancer cells, BITC and PEITC have been demonstrated to have anti-metastatic and anti-inflammatory effects against colon cancer, and it slowed the migration of colon cancer cells through the activation of p53 pathway ( 147 , 168 , 169 ).…”