OVERCOMING TNF-ALPHA AND CDDP RESISTANCE OF A HUMAN OVARIAN-CANCER CELL-LINE (C30) BY TREATMENT WITH BUTHIONINE SULFOXIMINE IN COMBINATION WITH TNF-ALPHA AND OR CDDP

  • Authors:
    • Y MIZUTANI
    • B BONAVIDA
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  • Published online on: August 1, 1993     https://doi.org/10.3892/ijo.3.2.229
  • Pages: 229-235
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Abstract

Previous studies have demonstrated that glutathione (GSH) plays an important role in a wide range of cellular functions including protection, detoxification, transport and metabolism. GSH has been implicated in tumor cell resistance to drugs and/or cytotoxic factors. Buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, depletes intracellular GSH and thus could reverse resistance. The present study investigated the effect of BSO used in combination with tumor necrosis factor-alpha (TNF-alpha) or cisdiamminedichloroplatinum (II) (CDDP) on cytotoxicity of a TNF-alpha and CDDP resistant human ovarian cancer cell line (C30). Cytotoxicity was monitored by the MTT assay. Treatment of C30 cells with BSO and CDDP or BSO and TNF-alpha resulted in overcoming resistance and a synergistic cytotoxic effect was obtained. Pretreatment of the tumor cells by either agent for 4 h and wash and followed by the addition of the second agent for 20 h resulted in the same cytotoxicity as observed in the presence of the two agents. Furthermore, combination treatment with BSO, CDDP and TNF-alpha further augmented the synergistic cytotoxic activity achieved by two agents against C30 cells. The protective effect of GSH was shown for TNF-alpha but not for CDDP as treatment of C30 cells with TNF-alpha in combination with GSH or N-acetyl-cysteine (NAC) reduced the cytotoxic effect of TNF-alpha. One mechanism of resistance to TNF-alpha in tumor cells is through the induction of TNF-alpha mRNA and/or protein. The C30 cells did not constitutively express TNF-alpha mRNA, however, treatment of C30 cells with TNF-alpha upregulated the expression of TNF-alpha mRNA. When BSO was used in combination with TNF-alpha, the level of TNF-alpha mRNA induced by TNF-alpha was markedly reduced. Further, incubation of C30 cells with TNF-alpha in conjunction with GSH or NAC also downregulated the expression of TNF-alpha mRNA induced by TNF-alpha. These findings demonstrate that treatment with BSO in combination with TNF-alpha or CDDP can overcome the resistance of C30 tumor cells to TNF-alpha and CDDP. The depletion of intracellular GSH and downregulation of TNF-alpha mRNA by BSO may play a role in the enhanced cytotoxicity seen with the combination of BSO and TNF-alpha. The synergistic effect obtained with a CDDP selected resistant ovarian cancer cell line suggests that treatment with BSO in conjunction with either TNF-alpha or CDDP, or TNF-alpha and CDDP may have a clinical application in the therapy of TNF-alpha and/or CDDP resistant ovarian tumors'

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August 1993
Volume 3 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
MIZUTANI Y and MIZUTANI Y: OVERCOMING TNF-ALPHA AND CDDP RESISTANCE OF A HUMAN OVARIAN-CANCER CELL-LINE (C30) BY TREATMENT WITH BUTHIONINE SULFOXIMINE IN COMBINATION WITH TNF-ALPHA AND OR CDDP. Int J Oncol 3: 229-235, 1993
APA
MIZUTANI, Y., & MIZUTANI, Y. (1993). OVERCOMING TNF-ALPHA AND CDDP RESISTANCE OF A HUMAN OVARIAN-CANCER CELL-LINE (C30) BY TREATMENT WITH BUTHIONINE SULFOXIMINE IN COMBINATION WITH TNF-ALPHA AND OR CDDP. International Journal of Oncology, 3, 229-235. https://doi.org/10.3892/ijo.3.2.229
MLA
MIZUTANI, Y., BONAVIDA, B."OVERCOMING TNF-ALPHA AND CDDP RESISTANCE OF A HUMAN OVARIAN-CANCER CELL-LINE (C30) BY TREATMENT WITH BUTHIONINE SULFOXIMINE IN COMBINATION WITH TNF-ALPHA AND OR CDDP". International Journal of Oncology 3.2 (1993): 229-235.
Chicago
MIZUTANI, Y., BONAVIDA, B."OVERCOMING TNF-ALPHA AND CDDP RESISTANCE OF A HUMAN OVARIAN-CANCER CELL-LINE (C30) BY TREATMENT WITH BUTHIONINE SULFOXIMINE IN COMBINATION WITH TNF-ALPHA AND OR CDDP". International Journal of Oncology 3, no. 2 (1993): 229-235. https://doi.org/10.3892/ijo.3.2.229