Binding to protein by isothiocyanates: a potential mechanism for apoptosis induction in human non small lung cancer cells.
The upstream events by which isothiocyanates (ITCs) induce apoptosis have not been fully investigated. Numerous studies have reported that the apoptosis was induced by ITCs through generation of reactive oxygen species (ROS) as a result of conjugating with and, consequently, depleting cellular glutathione. As electrophiles, ITCs could potentially trigger apoptosis by binding to macromolecules including DNA and proteins. The results showed that DNA damage may not be an important early event for the apoptosis induction by ITCs. Phenethyl isothiocyanate (PEITC) is a more potent inducer of apoptosis than sulforaphane (SFN) in A549 cells, but SFN induces more ROS generation and oxidative damages than PEITC, suggesting that oxidative stress again is probably not a trigger for apoptosis in these cells. In contrast, we found that PEITC binds more to intracellular proteins than SFN. We identified tubulin as 1 of the protein targets of ITCs through proteomics approach. We showed that the relative tubulin binding affinity of ITCs correlates well with their potency of cell growth inhibition and apoptosis induction. These results collectively suggest that the covalent binding to protein targets, such as tubulin, by ITCs is an important chemical event in apoptosis induction by ITCs in human lung A549 cells.
Mi
Lixin
L
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Chung
Fung-Lung
FL
D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003545:Cysteine / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress; D011485:Protein Binding; D050050:Protein Carbonylation / Q000187:drug effects; D013454:Sulfoxides; D013861:Thiocyanates / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D014404:Tubulin; C058305:phenethyl isothiocyanate; C031403:benzyl isothiocyanate; C016766:sulforaphane; D003545:Cysteine