Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
KB3-1 can be a MDR-reversal drug candidate for combination chemotherapy with TAX.
Koo
Jin-Suk
JS
Oriental Medical College, Kyunghee University, 1 Hoegidong, Dongdaemungu, Seoul 130-701, South Korea.
Choi
Won-Cheol
WC
Rhee
Yun-Hee
YH
Lee
Hyo-Jeong
HJ
Lee
Eun-Ok
EO
Ahn
Kwang Seok
KS
Bae
Hyun-Soo
HS
Ahn
Kyoo-Seok
KS
Kang
Jong-Min
JM
Choi
Sang-Un
SU
Kim
Myung Ok
MO
Lu
Junxuan
J
Kim
Sung-Hoon
SH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D017239:Paclitaxel / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D020112:Rhodamine 123; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D011804:Quinolines; D051028:bcl-2-Associated X Protein; C534719:quinoline-3-carboxylic acid (4-(2-(benzyl-3-((3,4-dimethoxyphenyl)propionyl)amino)ethyl)phenyl)amide; D020112:Rhodamine 123; D045304:Cytochromes c; D017239:Paclitaxel