Evaluation of Novel Sansalvamide A derivatives as Potential Anti-Cancer Agents
Shelli R. McAlpine, Ph.D.
Stephen B. Howell, M.D.
Cisplatin is one of the most important cancer chemotherapeutic agents. It is widely used for the treatment of ovarian, lung, head and neck, and several other types of tumors. However, almost all patients eventually become resistant to cisplatin due, in part, to a failure of the drug to enter the tumor cells. How this drug enters cells and is distributed to its sites of action within the cell is poorly understood. The overall goal of this project is to enhance the efficacy of cisplatin and develop ways of preventing or overcoming resistance by investigating the transporters that control drug influx and efflux. Trace amounts of copper are required by all cells, and CTR2 is a protein found on the surface of tumor cells that transports copper into the cell. We found that CTR2 also regulates the transport of cisplatin. We molecularly engineered tumor cells to decrease the level of CTR2 and found that this interfered with their ability to grow in mice, but surprisingly increased rather than decreased the uptake of cisplatin into tumors and its effectiveness in reducing tumor growth. In the second part of this study we sought to determine the mechanism of this effect and found that reduction of CTR2 increased a process called macropinocytosis, a well-known pathway by which cells acquire fluids and nutrients from their environment. We were able to show that CTR2 controls the activation of two of the proteins known to regulate macropinocytosis. The importance of these observations is that they identify CTR2 as a target through which it is possible to increase the effectiveness of cisplatin therapy.
Project Period: 9/1/2008 – 8/31/2011
Blair, B.G., Larson, C.A., Adams, P.L., Abada, P.B., Pesce, C.E., Safaei, R., Howell, S.B., Copper Transporter 2 (CTR2) regulates endocytosis and controls tumor growth and sensitivity to cisplatin in vivo, Mol Pharmacol, 79:157-66, 2011.
Vasko RC, Rodriguez RA, Cunningham C, Ardi V, Agard D, McAlpine SR. Mechanistic studies of Sansalvamide A-amide: An allosteric modulator of Hsp90 Communication Journal of American Chemical Society, 2010.
Blair, B.G., Larson, C.A., Adams, P.L., Abada, P.B., Safaei, R., Howell, S.B., Regulation of CTR2 Expression by Copper and Cisplatin in Human Ovarian Carcinoma Cells, Mol Pharmacol, 77:912-21, 2010. PMID: 20194531
Alexander, L.D., Sellers, R.P., Davis, M.R., Ardi, V.C.,Johnson, V.A., Vasko, R.C., and McAlpine, S.R. Evaluation of Di-Sansalvamide A derivatives: synthesis, SAR, and Mechanism of action Journal of Medicinal Chemistry (letter) v52, p7927-7930, 2009.
NIH/NCI 1 R01CA137873 (PI: Shelli McAlpine)