Open AccessZerumbone increases oxidative stress in a thiol‐dependent ROS ‐independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation
Author(s) -
Deorukhkar Amit,
Ahuja Niharika,
Mercado ArmandoLopez,
Diagaradjane Parmeswaran,
Raju Uma,
Patel Nalini,
Mohindra Pranshu,
Diep Nga,
Guha Sushovan,
Krishnan Sunil
Publication year - 2015
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.367
Subject(s) - reactive oxygen species , dna damage , apoptosis , oxidative stress , cancer research , colorectal cancer , glutathione , chemistry , radioresistance , dna repair , radiation therapy , cell cycle checkpoint , cell cycle , pharmacology , radiosensitivity , cancer , medicine , biochemistry , dna , enzyme
Locally advanced rectal cancers are treated with neoadjuvant chemoradiation therapy followed by surgery. In a minority (~20%) of patients, no tumor is present at the time of surgery; these patients with a complete pathologic response (path CR ) to neoadjuvant therapy have better treatment outcomes. Unfortunately, the inherent radioresistance of colorectal cancer ( CRC ) cells dictates that the majority of patients do not achieve a path CR . Efforts to improve these odds have fueled the search for novel, relatively less‐toxic radiosensitizers with distinct molecular mechanism(s) and broad‐spectrum anticancer activities. Here, we use zerumbone, a sesquiterpene from the edible ginger ( Zingiber zerumbet Smith), to enhance radiosensitivity of CRC cells. Short exposure to zerumbone (7 h) profoundly sensitized CRC cells, independent of their p53 or k ‐ RAS status. Zerumbone enhanced radiation‐induced cell cycle arrest (G2/M), increased radiation‐induced apoptosis, but induced little apoptosis by itself. Zerumbone significantly enhanced radiation‐induced DNA damage, as evident by delayed resolution of post‐irradiation nuclear γ H2 AX foci, whereas zerumbone treatment alone did not induce γ H2 AX foci formation. Zerumbone pretreatment inhibited radiation‐induced nuclear expression of DNA repair proteins ataxia‐telangiectasia mutated ( ATM ) and DNA ‐ PK cs. Interestingly, zerumbone‐mediated radiosensitization did not involve reactive oxygen species ( ROS ), but was mediated through depletion of cellular glutathione (GSH). Ability of only thiol‐based antioxidants to abrogate zerumbone‐mediated radiosensitization further corroborated this hypothesis. The α , β ‐unsaturated carbonyl group in zerumbone was found to be essential for its bioactivity as zerumbone analog α ‐Humulene that lacks this functional group, could neither radiosensitize CRC cells, nor deplete cellular GSH. Our studies elucidate novel mechanism(s) of zerumbone's ability to enhance CRC radiosensitivity.