[Sensitization of TRAIL–resistant cells by inhibition of HSP90 with low-dose geldanamycin ]
>>Mol Cancer Ther. 2006;5:170-178
Sensitization of TRAIL–resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin
Yulin Ma2, Vijayabaskar Lakshmikanthan2, Ronald W. Lewis2 and M. Vijay Kumar1,2
1 Department of Research, VA Medical Center and 2 Department of Surgery, Section of Urology, Medical College of Georgia, Augusta, Georgia
Requests for reprints: M. Vijay Kumar, Department of Research, VA Medical Center, One Freedom Way, Augusta, GA 30904. Phone: 706-721-6620; Fax: 706-721-2548. E-mail: vkumar@mail.mcg.edu
Due to its specificity and effectiveness, tumor necrosis factor-–related apoptosis-inducing ligand (TRAIL) is being tested for cancer therapy. Inhibition of the function of heat shock protein 90 (HSP90) is under clinical trials for cancer therapy. However, some cancer cells are resistant to TRAIL, and at the dose required for inducing apoptosis, geldanamycin, a drug that inhibits HSP90 function, has shown adverse effects. Therefore, our working plan was to identify a sublethal dose of geldanamycin and combine it with TRAIL to induce apoptosis in TRAIL-resistant prostate cancer cells. Treatment of LNCaP with 250 nmol/L geldanamycin inhibited HSP90 function but did not induce significant apoptosis. However, combination of geldanamycin and TRAIL induced highly significant apoptosis in TRAIL-resistant LNCaP cells. In addition to inducing caspase activity and apoptosis, treatment with geldanamycin and TRAIL decreased inhibitor of B (IB) kinase (IKK) complex proteins, IKK, IKKß, and IKK. The loss of IKK affected IB/nuclear factor-B (NF-B) interaction and reduced nuclear transport of NF-B, resulting in reduced NF-B activity. Our data show increase in apoptosis using low, suboptimal dose of geldanamycin when used with TRAIL. These results provide a means to alleviate two problems: resistance to TRAIL and adverse effects of high-dose geldanamycin.<<
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