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ABSTRACT: A promising family of anticancer agents, the camptothecins, is noted for their ability to induce apoptosis specifically in malignant cells. However, a major obstacle for successful cancer treatment by these and other chemotherapeutic agents is the intrinsic or acquired resistance to drug treatment. Resistance to 9NC6, a camptothecin derivative, has been modeled in vitro using a human prostate cancer cell line. To elucidate the mechanism for acquired 9NC resistance, we have used a subtractive cloning approach to identify genes whose altered expression level is reflective of 9NC resistance or susceptibility. Differential gene expression was compared between wild-type human prostate cancer cell line, DU-145, and a 9NC-resistant subline, RC1. Results were confirmed by Northern and Western blot analyses. In this report, we focus on one gene, 14-3-3zeta. An expression vector of a full-length myc-epitope-tagged 14-3-3zeta cDNA was constructed and used for transfection into DU-145 cells. We consistently observed that 14-3-3zeta message and protein levels were dramatically increased in 9NC resistant cells. The expression levels of other 14-3-3 family members were unaffected. Strikingly, ectopic overexpression of 14-3-3zeta in wild-type 9NC-susceptible prostate cancer cells decreased 9NC-induced apoptosis. Our results suggest a novel direct or indirect role of 14-3-3zeta in mediating resistance of DU-145 cells to the topoisomerase I inhibitor, 9NC. We are currently exploring whether this represents a more general pathway for drug resistance as well.
International Journal of Oncology 09/2004; 25(2):503-9. · 2.40 Impact Factor
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Devasis Chatterjee,
Yin Bai,
Zhe Wang,
Sandy Beach,
Stephanie Mott,
Rajat Roy,
Corey Braastad,
Yaping Sun,
Asok Mukhopadhyay,
Bharat B Aggarwal, James Darnowski,
Panayotis Pantazis,
James Wyche,
Zheng Fu,
Yasuhide Kitagwa,
Evan T Keller,
John M Sedivy,
Kam C Yeung
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ABSTRACT: Cancer cells are more susceptible to chemotherapeutic agent-induced apoptosis than their normal counterparts. Although it has been demonstrated that the increased sensitivity results from deregulation of oncoproteins during cancer development (Evan, G. I., and Vousden, K. H. (2001) Nature 411, 342-348; Green, D. R., and Evan, G. I. (2002) Cancer Cell 1, 19-30), little is known about the signaling pathways leading to changes in the apoptotic threshold in cancer cells. Here we show that low RKIP expression levels in tumorigenic human prostate and breast cancer cells are rapidly induced upon chemotherapeutic drug treatment, sensitizing the cells to apoptosis. We show that the maximal RKIP expression correlates perfectly with the onset of apoptosis. In cancer cells resistant to DNA-damaging agents, treatment with the drugs does not up-regulate RKIP expression. However, ectopic expression of RKIP resensitizes DNA-damaging agent-resistant cells to undergo apoptosis. This sensitization can be reversed by up-regulation of survival pathways. Down-regulation of endogenous RKIP by expression of antisense and small interfering RNA (siRNA) confers resistance on sensitive cancer cells to anticancer drug-induced apoptosis. Our studies suggest that RKIP may represent a novel effector of signal transduction pathways leading to apoptosis and a prognostic marker of the pathogenesis of human cancer cells and tumors after treatment with clinically relevant chemotherapeutic drugs.
Journal of Biological Chemistry 05/2004; 279(17):17515-23. · 4.77 Impact Factor
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ABSTRACT: The antibacterial agent taurolidine (TRD) has been used as a lavage antibiotic to prevent development of peritonitis in patients after surgery. We recently showed that TRD induced growth arrest and apoptosis of a variety of cultured cell lines derived from human solid tumors and also significantly inhibited the growth of human ovarian tumors in a mouse model. In this report, we present data to show that TRD, at concentrations below the doses that are used to treat patients in the clinic, induces apoptosis of human leukemia HL-60 cells by a mitochondrial cytochrome c-dependent pathway.
Anticancer research 22(4):1959-64. · 1.73 Impact Factor
