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Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells.
Life Sci. 2008 Nov 21; 83(21-22):700-8.LS

Abstract

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 microM and 3 microM. 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 microM had comparable MDR-reversal activity to 10 microM verapamil, a well-known MDR- reversal agent.

SIGNIFICANCE

KB3-1 can be a MDR-reversal drug candidate for combination chemotherapy with TAX.

Authors+Show Affiliations

Oriental Medical College, Kyunghee University, 1 Hoegidong, Dongdaemungu, Seoul 130-701, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18845169

Citation

Koo, Jin-Suk, et al. "Quinoline Derivative KB3-1 Potentiates Paclitaxel Induced Cytotoxicity and Cycle Arrest Via Multidrug Resistance Reversal in MES-SA/DX5 Cancer Cells." Life Sciences, vol. 83, no. 21-22, 2008, pp. 700-8.
Koo JS, Choi WC, Rhee YH, et al. Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells. Life Sci. 2008;83(21-22):700-8.
Koo, J. S., Choi, W. C., Rhee, Y. H., Lee, H. J., Lee, E. O., Ahn, K. S., Bae, H. S., Ahn, K. S., Kang, J. M., Choi, S. U., Kim, M. O., Lu, J., & Kim, S. H. (2008). Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells. Life Sciences, 83(21-22), 700-8. https://doi.org/10.1016/j.lfs.2008.09.009
Koo JS, et al. Quinoline Derivative KB3-1 Potentiates Paclitaxel Induced Cytotoxicity and Cycle Arrest Via Multidrug Resistance Reversal in MES-SA/DX5 Cancer Cells. Life Sci. 2008 Nov 21;83(21-22):700-8. PubMed PMID: 18845169.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells. AU - Koo,Jin-Suk, AU - Choi,Won-Cheol, AU - Rhee,Yun-Hee, AU - Lee,Hyo-Jeong, AU - Lee,Eun-Ok, AU - Ahn,Kwang Seok, AU - Bae,Hyun-Soo, AU - Ahn,Kyoo-Seok, AU - Kang,Jong-Min, AU - Choi,Sang-Un, AU - Kim,Myung Ok, AU - Lu,Junxuan, AU - Kim,Sung-Hoon, Y1 - 2008/09/24/ PY - 2008/08/06/received PY - 2008/09/02/accepted PY - 2008/10/11/pubmed PY - 2009/2/3/medline PY - 2008/10/11/entrez SP - 700 EP - 8 JF - Life sciences JO - Life Sci VL - 83 IS - 21-22 N2 - 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 microM and 3 microM. 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 microM had comparable MDR-reversal activity to 10 microM verapamil, a well-known MDR- reversal agent. SIGNIFICANCE: KB3-1 can be a MDR-reversal drug candidate for combination chemotherapy with TAX. SN - 0024-3205 UR - https://www.unboundmedicine.com/medline/citation/18845169/Quinoline_derivative_KB3_1_potentiates_paclitaxel_induced_cytotoxicity_and_cycle_arrest_via_multidrug_resistance_reversal_in_MES_SA/DX5_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(08)00372-X DB - PRIME DP - Unbound Medicine ER -