title: UMMS-4 enhanced sensitivity of chemotherapeutic agents to ABCB1-overexpressing cells via inhibiting function of ABCB1 transporter.
abstract: Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters through efflux of antineoplastic agents from cancer cells is a major obstacle to successful cancer chemotherapy. The inhibition of these ABC transporters is thus a logical approach to circumvent MDR. There has been intensive research effort to design and develop novel inhibitors for the ABC transporters to achieve this goal. In the present study, we evaluated the ability of UMMS-4 to modulate P-glycoprotein (P-gp/ABCB1)-, breast cancer resistance protein (BCRP/ABCG2)- and multidrug resistance protein (MRP1/ABCC1)-mediated MDR in cancer cells. Our findings showed that UMMS-4, at non-cytotoxic concentrations, apparently circumvents resistance to ABCB1 substrate anticancer drugs in ABCB1-overexpressing cells. When used at a concentration of 20 μmol/L, UMMS-4 produced a 17.53-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive parental cells. UMMS-4, however, did not significantly alter the sensitivity of non-ABCB1 substrates in all cells and was unable to reverse ABCG2- and ABCC1-mediated MDR. Additionally, UMMS-4 profoundly inhibited the transport of rhodamine 123 (Rho 123) and doxorubicin (Dox) by the ABCB1 transporter. Furthermore, UMMS-4 did not alter the expression of ABCB1 at the mRNA and protein levels. In addition, the results of ATPase assays showed that UMMS-4 stimulated the ATPase activity of ABCB1. Taken together, we conclude that UMMS-4 antagonizes ABCB1-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1. These findings may be useful for the development of safer and more effective MDR modulator.
authors.affiliation: Department of Chemistry, College of Life Science and Technology, Jinan University Guangzhou, China ; Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Guangzhou, China.
authors.forename: Dongjuan
authors.initials: D
authors.lastname: Qiao
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Guangzhou, China ; Department of General Surgery, Chen Xing Hai Hospital, Guangdong Medical College Zhongshan, China.
authors.forename: Shangjun
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Chemistry, Government College Women University Faisalabad, Pakistan.
authors.forename: Sana
authors.initials: S
authors.lastname: Aslam
authors.affiliation: Department of Chemistry, Government College Universit Faisalabad-38000, Pakistan.
authors.forename: Matloob
authors.initials: M
authors.lastname: Ahmad
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong Hong Kong SAR, China.
authors.forename: Kenneth Kin Wah
authors.initials: KK
authors.lastname: To
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Guangzhou, China.
authors.forename: Zhencong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Chemistry, College of Life Science and Technology, Jinan University Guangzhou, China.
authors.forename: Jiye
authors.initials: J
authors.lastname: Cai
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Guangzhou, China.
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
keywords: ABCB1; ATP binding cassette transporters; UMMS-4; chemotherapeutic drugs; multidrug resistance