Sensitization of TRAIL-resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin.
Due to its specificity and effectiveness, tumor necrosis factor-alpha-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 kappaB (IkappaB) kinase (IKK) complex proteins, IKKalpha, IKKbeta, and IKKgamma. The loss of IKK affected IkappaBalpha/nuclear factor-kappaB (NF-kappaB) interaction and reduced nuclear transport of NF-kappaB, resulting in reduced NF-kappaB 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.
Ma
Yulin
Y
Department of Surgery, Section of Urology, Medical College of Georgia, Augusta, GA, USA.
Lakshmikanthan
Vijayabaskar
V
Lewis
Ronald W
RW
Kumar
M Vijay
MV
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D016227:Benzoquinones; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000187:drug effects / Q000378:metabolism; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D047029:Lactams, Macrocyclic; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011809:Quinones / Q000008:administration & dosage / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D020672:I-kappa B Proteins; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011809:Quinones; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; C001277:geldanamycin