國家衛生研究院 NHRI:Item 3990099045/5545

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Title:	Combined modalities of resistance in a cisplatin-driven human betel-associated oral squamous cell carcinoma
Authors:	Cheng, Y;Chen, H;Hsiao, J;Chen, L;Chang, J;Kuo, C
Contributors:	National Institute of Cancer Research
Abstract:	Betel nut is an important etiological factor associated with the high prevalence of oral squamous cell carcinoma (OSCC) in Southeast Asia. Squamous cell carcinoma is the most frequent head and neck cancers and cisplatin is the most commonly used chemotherapeutic regimen either alone or a combination with other drugs. To clarify mechanisms of the resistance to cisplatin, we developed a cisplatin-driven drug resistant line, OECM1-Su2, from betel-associated OSCC cell line, OECM1, by continuous selection against accumulating drug concentrations. Compared with the parental cells, the OECM1-Su2 cells showed 4-fold resistance to cisplatin and over 1.5-fold resistance to carboplatin, while both cell lines with a similar degree of sensitivity to arsenic trioxide. Interestingly, OECM1-Su2 cells were 27-fold apparently resistant to oxaliplatin. Because platinum agents destroy cancerous cells by interfering with DNA, the frequency of DNA double-strand breaks (DSB) in both cells were determined and we found that the level of cH2AX, a marker of DSBs, in OECM1 cells was higher than that in OECM1-Su2 cells. The protein level of DNA repair protein XRCC1 (X-ray repair cross complementing protein 1) was increased in OECM1-Su2 cells compared with the parental cells. Reduced glutathione (GSH) has been addressed an important determinant for platinum resistance and GSH synthetic/metabolic enzymes were the targets for Nrf2 (NF-E2-related factor-2) regulated via Nrf2/Keap1 pathway. OECM1-Su2 cells displayed about a 2-fold higher cellular level of GSH, correlated with increasing protein amounts of Nrf2, than OECM1 cells. Furthermore, Nrf2 negative mediator Keap1 decreased the expression level in OECM1-Su2 cells compared with OECM1 cells. Taken together, our results suggested that the mechanism responsible for cisplatin resistance in betel-associated OSCC is the combination of increased DNA repair and activation of Nrf2/Keap1 pathway.
Date:	2010-10
Relation:	Annals of Oncology. 2010 Oct;21(Suppl. 8):52.
Link to:	http://dx.doi.org/10.1093/annonc/mdq513
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0923-7534&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000283115900133
Appears in Collections:	[Ching-Chuan Kuo] Conference Papers/Meeting Abstract [Jang-Yang Chang] Conference Papers/Meeting Abstract [Li-Tzong Chen] Conference Papers/Meeting Abstract

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