Selective toxicity of NSC73306 in MDR1-positive cells as a new strategy to circumvent multidrug resistance in cancer

被引:154
作者
Ludwig, Joseph A. [1 ]
Szakacs, Gergely [1 ]
Martin, Scott E. [1 ]
Chu, Benjamin F. [1 ]
Cardarelli, Carol [1 ]
Sauna, Zuben E. [1 ]
Caplen, Natasha J. [1 ]
Fales, Henry M. [1 ]
Ambudkar, Suresh V. [1 ]
Weinstein, John N. [1 ]
Gottesman, Michael M. [1 ]
机构
[1] Hungarian Acad Sci, Inst Enzymol, Biol Res Ctr, Budapest, Hungary
关键词
D O I
10.1158/0008-5472.CAN-05-3322
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
ATP-binding cassette (ABC) proteins include the best known mediators of resistance to anticancer drugs. In particular, ABCB1 [MDR1/P-glycoprotein (P-gp)] extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. Attempts to overcome P-gp-mediated drug resistance using specific inhibitors of P-gp has had limited success and has faced many therapeutic challenges. As an alternative approach to using P-gp inhibitors, we characterize a thiosemicarbazone derivative (NSC73306) identified in a generic screen as a compound that exploits, rather than suppresses, P-gp function to induce cytotoxicity. Cytotoxic activity of NSC73306 was evaluated in vitro using human epidermoid, ovarian, and colon cancer cell lines expressing various levels of P-gp. Our findings suggest that cells become hypersensitive to NSC73306 in proportion to the increased P-gp function and multidrug resistance (MDR). Abrogation of both sensitivity to NSC73306 and resistance to P-gp substrate anticancer agents occurred with specific inhibition of P-gp function using either a P-gp inhibitor (PSC833, XR9576) or RNA interference, suggesting that cytotoxicity was linked to MDR1 function, not to other, nonspecific factors arising during the generation of resistant or transfected cells. Molecular characterization of cells selected for resistance to NSC73306 revealed loss of P-gp expression and consequent loss of the MDR phenotype. Although hypersensitivity to NSC73306 required functional expression of P-gp, biochemical assays revealed no direct interaction between NSC73306 and P-gp. This article shows that NSC73306 kills cells with intrinsic or acquired P-gp-induced MDR and indirectly acts to eliminate resistance to MDR1 substrates.
引用
收藏
页码:4808 / 4815
页数:8
相关论文
共 48 条
[41]   Cell line designation change: Multidrug-resistant cell line in the NCI anticancer screen [J].
Scudiero, DA ;
Monks, A ;
Sausville, EA .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1998, 90 (11) :862-862
[42]  
SHEN DW, 1986, J BIOL CHEM, V261, P7762
[43]   Predicting drug sensitivity and resistance:: Profiling ABC transporter genes in cancer cells [J].
Szakács, G ;
Annereau, JP ;
Lababidi, S ;
Shankavaram, U ;
Arciello, A ;
Bussey, KJ ;
Reinhold, W ;
Guo, YP ;
Kruh, GD ;
Reimers, M ;
Weinstein, JN ;
Gottesman, MM .
CANCER CELL, 2004, 6 (02) :129-137
[44]   Role of glycine-534 and glycine-1179 of human multidrug resistance protein (MDR1) in drug-mediated control of ATP hydrolysis [J].
Szakács, G ;
Özvegy, C ;
Bakos, É ;
Sarkadi, B ;
Váradi, A .
BIOCHEMICAL JOURNAL, 2001, 356 (01) :71-75
[45]   USE OF RECOMBINANT P-GLYCOPROTEIN FRAGMENTS TO PRODUCE ANTIBODIES TO THE MULTIDRUG TRANSPORTER [J].
TANAKA, S ;
CURRIER, SJ ;
BRUGGEMANN, EP ;
UEDA, K ;
GERMANN, UA ;
PASTAN, I ;
GOTTESMAN, MM .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1990, 166 (01) :180-186
[46]   EXPRESSION OF A FULL-LENGTH CDNA FOR THE HUMAN MDR1 GENE CONFERS RESISTANCE TO COLCHICINE, DOXORUBICIN, AND VINBLASTINE [J].
UEDA, K ;
CARDARELLI, C ;
GOTTESMAN, MM ;
PASTAN, I .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (09) :3004-3008
[47]  
Wu H, 2003, CANCER RES, V63, P1515
[48]   MULTIDRUG-RESISTANCE IN LYMPHOMAS [J].
YUEN, AR ;
SIKIC, BI .
JOURNAL OF CLINICAL ONCOLOGY, 1994, 12 (11) :2453-2459