Role of Membrane Ion Transport in Cisplatin Accumulation
Cisplatin (DDP) accumulation into cells cannot be explained by passive diffusion alone. Accumulation can be modulated by energy poisons, ion concentrations, cAMP levels, osmotic strength, protein kinase C agonists, ras expression, and calmodulin antagonists1–9. Although this evidence argues for the existence of a DDP transporter, the findings that DDP accumulation cannot be saturated nor competitively inhibited with structural analogues imply that a direct carrier is not involved in DDP transport4,10–12. The observation that decreased DDP accumulation is a frequent change in cells selected for DDP-resistance in vitro suggests that the DDP accumulation mechanism might be an important determinant of the cellular response to DDP1. The biochemical basis for this decrease is not known. Our studies have been focused on the elucidation of the process by which DDP enters cells and how this has changed in resistant cells. We have found that DDP-resistant human ovarian carcinoma cells with accumulation defects have alterations in their ion transport properties. We present evidence that suggests that these changes may be linked to the DDP accumulation defect in these cells.
KeywordsMembrane Potential Clonogenic Assay Membrane Potential Change Human Ovarian Carcinoma Cell Human Ovarian Carcinoma Cell Line
Unable to display preview. Download preview PDF.
- 3.Andrews, P.A., Mann, S.C., Huynh, H.H., and Albright, K.D. Role of Na+, K+-adenosine triphosphatase in the accumulation of cis-diamminedichloroplatinum(II) in human ovarian carcinoma cells. Cancer Res., In Press, 1991.Google Scholar
- 4.Andrews, P.A., Mann, S.C., Velury, S., and Howell, S.B. Cisplatin uptake mediated cisplatin-resistance in human ovarian carcinoma cells. In: M. Nicolini (ed.), Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy, pp. 248–254. Boston, MA: Martinus Nijhoff, 1988.CrossRefGoogle Scholar
- 5.Mann, S.C., Andrews, P.A., and Howell, S.B. Role of protein kinase A in the modulation of cisplatin accumulation in human ovarian carcinoma cells. Proc. Am. Assoc. Cancer Res., 31:404, 1990.Google Scholar
- 8.Isonishi, S., Andrews, P.A., Howell, S.B., and Lazo, J. Overexpression of ras oncogene confers resistance to cisplatin. Proc. Am. Assoc. Cancer Res., 31:360, 1990.Google Scholar
- 9.Kikuchi, Y., Iwano, I., Miyauchi, M., Sasa, H., Nagata, I., and Kuki, E. Restorative effects of calmodulin antagonists on reduced cisplatin uptake by cisplatin-resistant human ovarian cancer cells. Gynecol. Oncol., 39:199–203, 1990.Google Scholar
- 10.Mann, S.C., Andrews, P.A., and Howell, S.B. Short-term cis-diamminedichloroplatinum(II) accumulation in sensitive and resistant human ovarian carcinoma cells. Cancer Chemother. Pharmacol., 25:236–240, 1990.Google Scholar
- 13.Andrews, P.A., Jones, J.A., Varki, N.M., and Howell, S.B. Rapid emergence of acquired cis-diamminedichloroplatinum(II) resistance in an in vivo model of human ovarian carcinoma. Cancer Comm., 2:93–100, 1990.Google Scholar