Zerumbone increases oxidative stress in a thiol‐dependent ROS‐independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation

Abstract

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 (pathCR) 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 pathCR. 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 γH2AX foci, whereas zerumbone treatment alone did not induce γH2AX foci formation. Zerumbone pretreatment inhibited radiation-induced nuclear expression of DNA repair proteins ataxia-telangiectasia mutated (ATM) and DNA-PKcs. 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.

Protective Effects of Zerumbone on Colonic Tumorigenesis in Enterotoxigenic Bacteroides fragilis (ETBF)-Colonized AOM/DSS BALB/c Mice

“…Regarding zerumbone effects on colorectal cancer cell lines, zerumbone decreased expressed of cFLIP, which in turn stimulated TRAIL death receptor DR4 and DR5, augmenting TRAIL-induced apoptosis in HCT116 colon cancer cell line [22]. The zerumbone treatment also leads to cell cycle arrest and increased apoptosis in three colorectal cell lines (HCT116, SW620 and HT29) [30]. Mice injected with AOM and given DSS, oral zerumbone treatment for 17 weeks resulted in decreased colon inflammation and colon polyp formation through inhibition of NF-κB and heme oxygenase-1 [31].…”

In vitro stimulatory effect of N‐acetyl tryptophan‐glucopyranoside against gamma radiation induced immunosuppression

“…NATG at 0.25 μg/mL exhibited maximum colony formation, as compared with other tested doses, when given prior (–2 hours) to γ–irradiation (Figure ). Such augmentation in cell proliferation rate against radiation damage could be the result of several factors, such as inhibition of free radical generation, repair of damaged DNA, protection of cell membrane and an increase in the reproducing ability of cells …”

Protective Effect of Montelukast against Cadmium Induced Pituitary Gland Toxicity

“…P53 gene is one of them. It presents at a low level in the normal cellular environment but under stressful conditions as excess reactive oxygen species and DNA damage, p53 increases to stop cell growth, repair DNA or if fail, cell death occurs [37]. There are several mechanisms involved in the apoptotic effect of Cd.…”