Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells.
Koo, Jin-Suk a; Choi, Won-Cheol a; Rhee, Yun-Hee a; Lee, Hyo-Jeong a; Lee, Eun-Ok a; Ahn, Kwang Seok a; Bae, Hyun-Soo a; Ahn, Kyoo-Seok a; Kang, Jong-Min b; Choi, Sang-Un c; Kim, Myung Ok d; Lu, Junxuan e; Kim, Sung-Hoon a,*
[Article]
Life Sciences.
83(21):700-708, November 2008.
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Aims: The resistance to chemotherapeutic drugs is a major problem for successful cancer treatment. Multidrug resistance (MDR) phenotype is characterized by over-expression of P-glycoprotein (P-gp) on the cancer cell plasma membrane that extrudes drugs out of the cells. Therefore, novel MDR reversal agents are desirable for combination therapy to reduce MDR and enhance anti-tumor activity. Thus, the present study was aimed to evaluate the potent efficacy of novel quinoline derivative KB3-1 as a potent MDR-reversing agent for combined therapy with TAX.
Main methods: MDR reversing effect and TAX combined therapy were examined by Rhodamine accumulation and efflux assay and Confocal immunofluorescence microscopy, Western blotting, TUNEL assay, and cell cycle analysis.
Key findings: The discovery of quinoline-3-carboxylic acid [4-(2-{benzyl-3[-(3,4-dimethoxy-phenyl)-propionyl]-amino}-ethyl)-phenyl]-amide (KB3-1) as a novel MDR-reversal agent. KB3-1 significantly enhanced the accumulation and retention of a P-gp substrate, rhodamine-123 in the P-gp-expressing MES-SA/DX5 uterine sarcoma cells but not in the P-gp-negative MES-SA cells at non-toxic concentrations of 1 [mu]M and 3 [mu]M. Similarly, fluorescence microscopy observation revealed that KB3-1 reduced the effluxed rhodamine-123 expression on the membrane of MES-SA/DX5 cells. Consistent with decreased P-gp pumping activity, confocal microscopic observation revealed that KB3-1 effectively diminished the expression of P-gp in paclitaxel (TAX)-treated MES-SA/DX-5 cells. Furthermore, Western blotting confirmed that KB3-1 reduced P-gp expression and enhanced cytochrome C release and Bax expression in TAX treated MES-SA/DX-5 cells. In addition, KB3-1 enhanced TAX-induced apoptotic bodies in MES-SA/DX5 cells by TdT-mediated-dUTP nick-end labeling (TUNEL) staining assay aswell as potentiated TAX- induced cytotoxicity, G2/M phase arrest and sub-G1 apoptosis in MES-SA/DX5 cells but not in MES-SA cells. Interestingly, KB3-1 at 3 [mu]M had comparable MDR-reversal activity to 10 [mu]M verapamil, a well-known MDR- reversal agent.
Significance: KB3-1 can be a MDR-reversal drug candidate for combination chemotherapy with TAX.
(C) 2008Elsevier, Inc.