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대장암 세포에서 다약물 내성기전으로서 ATP-Binding Cassette (ABC) Transporters의 발현과 기능

Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Colon Cancer Cells

대한대장항문학회지 2005년 21권 3호 p.129 ~ 137
정귀애 ( Jeong Gui-Ae ) - 조선대학교 의과대학 외과학교실

김경종 ( Kim Kyung-Jong ) - 조선대학교 의과대학 외과학교실
민영돈 ( Min Young-Don ) - 조선대학교 의과대학 외과학교실
이태범 ( Lee Tae-Bum ) - 조선대학교 의과대학 내성세포연구센터
강성인 ( Kang Sung-In ) - 조선대학교 의과대학 약리학교실
정권율 ( Jung Kwon-Ryul ) - 조선대학교 의과대학 약리학교실
최철희 ( Choi Chul-Hee ) - 조선대학교 의과대학 약리학교실

Abstract


Purpose: Multidrug resistance (MDR) is a phenomenon whereby tumor cells acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that concerned with altered membrane transporters in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast-cancer-resistance protein (BCRP) are well-known membrane transporters that pump out antitumor agents by using an ATP-dependent process, the so-called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter and to determine which transporter has functional acitivity in various colon cancer cells.

Methods: Expressions of Pgp, MRP, and BCRP mRNA were determined in 9 colon-cancer cell lines by using an RT-PCR assay. The sensitivity to anticancer agents substrate for each ABC transporter in the colon cancer cells determined using an MTT assay. The accumulation of fluorescent compounds for functional detection of each ABC transporter was determined by using flow cytometry.

Results: Pgp mRNA was variably expressed in 6 of 9 colon cancer cells lines. MRP and BCRP mRNA were expressed in all the 9 cell lines. A smaller cytotoxic effect to paclitaxel and a smaller amount of rhodamine123 accumulation were observed in Colo 320HSR expressing the highest levels of Pgp than in SNU-C5 not expressing Pgp. These effects in Colo320HSR were reversed with the addition of various Pgp inhibitors, but such a reversal did not occur in SNU-C5. The cytotoxic effect to VP-16 was not related to the expression levels of MRP in Colo320HSR and SNU-C, but the amount of calcein-AM accumulation was reversed with addition of probenecid, MRP inhibitor. The cytotoxic effect and the drug accumulation of mitoxantrone were not related to the expression levels of BCRP.

Conclusions: This study suggests that of the ABC transporters, primarily Pgp and MRP have functional activity in colon cancer cell lines. J Korean Soc Coloproctol 2005;21:129-137

키워드

대장암;다약물 내성;ATP 결합카세트 transporter
Colon cancer;Multidrug resistance (MDR);ABC transporter
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