Study of Quinazolinone Derivatives on Enhancement of Anticancer Drugs Activity

• Main Authors: LIN, CHUN-HUNG, 林俊宏
• Other Authors: Churn-Shiouh Gau
• Format: Others
• Language: zh-TW
• Published: 1998
• Online Access: http://ndltd.ncl.edu.tw/handle/30968119740447194201

碩士 === 國立臺灣大學 === 藥學系研究所 === 86 === ABSTRACT We have evaluated the effect of the quinazolinone derivatives on P-glycoprotein-mediated MDR in breast cancer by performing an in vitro cytotoxicity assay and flow cytometry. The cell lines employed for this study were human breast cancer cells selected for resistance to adriamycin, MCF7/adr, and its counterpart, wildtype MCF7. Compared with the sensitivity of the wildtype and adr-resistant cells, the MCF7/adr subline showed more than a sevenfold increase in resistance to adriamycin at 1uM. We have used the p air of MCF7 cells to assess the cytotoxic activity of a series of quinazolinone derivatives. In both cell lines, DQ-181 was the most potent cytotoxic agent using MTT assay, while the other compounds did not present significant activity. When the pair of MCF7 cells were treated with adriamycin, DQ-150 and EY-057 at 1uM could enhance cytotoxic activity of adriamycin in MCF7/adr, indicating that these compounds could reverse drug resistance induced by adriamycin. For investigation of the mechanism of DQ-150 and EY-057 on drug resistance reversal, rhodamine 123 accumulation was detected in the pair of MCF7 cells. One uM DQ-150 has a twofold increase in intracellular rhodamine 123 in MCF7/adr cells, compared with the control. In contrast, we did not observe the high level of rhodamine 123 accumulation in the pair of MCF7 cells treated with EY-057 at 1uM. In addition to enhancement of anticancer drug transportation, other mechanisms of drug resistance reversal have been studied. Apoptosis is the end point of cells exposed to chemotherapeutic agents and is part of normal homeostasis. In our study, an increase in apoptosis was observed in adriamycin-treated MCF7/ adr cells when exposed to DQ-150 or EY-057 for 4 days using flow cytometry. DQ-150 and EY-057 at 1uM could enhance apoptosis by a 3-fold and 1.5-fold, respectively, in MCF7/adr treated with adriamycin. sults demonstrates that DQ-150 or EY-057 sensitize the in vitro cytotoxicity of adriamycin in MCF7/adr cells. The mechanisms of drug resistance reversal may vary, depending on the structure of compounds. DQ-150 increases the intracellular accumulation of rhodamine 123 in MCF7/adr, Results demonstrates that DQ-150 or EY-057 sensitize the in vitro cytotoxicity of adriamycin in MCF7/adr cells. The mechanisms of drug resistance reversal may vary, depending on the structure of compounds. DQ-150 increases the intracellular accumulation of rhodamine 123 in MCF7/adr, indicating DQ-150 potentially reverse multidrug resistance through inhibition of the drug-efflux pump. EY-057 may activate the alternative pathways to reverse MDR, since rhodamine accumulation was not observed in MCF7/adr tre ated with EY-057. Enhancement of apoptosis in adriamycin- treated MCF7/adr cells is a common step for DQ-150 and EY-057 to achieve drug resistance reversal. Our study may create a novel group of anticancer drug sensitizers in breast cancer.