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

Joseph A. Ludwig, G. Szakács, Scott E. Martin, Benjamin F. Chu, Carol Cardarelli, Zuben E. Sauna, Natasha J. Caplen, Henry M. Fales, Suresh V. Ambudkar, John N. Weinstein, Michael M. Gottesman

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4808-4815
Number of pages8
JournalCancer Research
Volume66
Issue number9
DOIs
Publication statusPublished - May 1 2006

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Multiple Drug Resistance
P-Glycoprotein
Neoplasms
Thiosemicarbazones
RNA Interference
Drug Resistance
Pharmaceutical Preparations
Antineoplastic Agents
Ovarian Neoplasms
Colonic Neoplasms
Carrier Proteins
Hypersensitivity
Adenosine Triphosphate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Selective toxicity of NSC73306 in MDR1-positive cells as a new strategy to circumvent multidrug resistance in cancer. / Ludwig, Joseph A.; Szakács, G.; Martin, Scott E.; Chu, Benjamin F.; Cardarelli, Carol; Sauna, Zuben E.; Caplen, Natasha J.; Fales, Henry M.; Ambudkar, Suresh V.; Weinstein, John N.; Gottesman, Michael M.

In: Cancer Research, Vol. 66, No. 9, 01.05.2006, p. 4808-4815.

Research output: Contribution to journalArticle

Ludwig, JA, Szakács, G, Martin, SE, Chu, BF, Cardarelli, C, Sauna, ZE, Caplen, NJ, Fales, HM, Ambudkar, SV, Weinstein, JN & Gottesman, MM 2006, 'Selective toxicity of NSC73306 in MDR1-positive cells as a new strategy to circumvent multidrug resistance in cancer', Cancer Research, vol. 66, no. 9, pp. 4808-4815. https://doi.org/10.1158/0008-5472.CAN-05-3322
Ludwig, Joseph A. ; Szakács, G. ; Martin, Scott E. ; Chu, Benjamin F. ; Cardarelli, Carol ; Sauna, Zuben E. ; Caplen, Natasha J. ; Fales, Henry M. ; Ambudkar, Suresh V. ; Weinstein, John N. ; Gottesman, Michael M. / Selective toxicity of NSC73306 in MDR1-positive cells as a new strategy to circumvent multidrug resistance in cancer. In: Cancer Research. 2006 ; Vol. 66, No. 9. pp. 4808-4815.
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AU - Sauna, Zuben E.

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