towards improved death receptor targeted therapy for ... - TI Pharma
towards improved death receptor targeted therapy for ... - TI Pharma towards improved death receptor targeted therapy for ... - TI Pharma
Chapter 5 Inhibition of Hsp90 by 17‐AAG enhances TRAIL‐induced apoptosis in non‐small cell lung cancer cells. Kaamar Azijli, Saravanan Yuvaraj, Sjors Kas, Godefridus J. Peters, Steven de Jong, Frank A.E. Kruyt Submitted for publication
Chapter 5 ABSTRACT TRAIL is an interesting cancer therapeutic agent, because of its capability of inducing apoptosis selectively in tumor cells. Unfortunately, half of the NSCLC cells are resistant to TRAIL‐induced apoptosis. The rational combination of TRAIL with other agents is known to provide an effective strategy to increase the cell killing potential of TRAIL. Here, we show that targeting Hsp90, an important heat shock protein in the tumorigenesis of NSCLC, with 17‐AAG increased TRAIL‐induced apoptosis in TRAIL sensitive H460 and resistant A549 cells. The combination index (CI), determined from MTT growth inhibition assays for combined treatment with TRAIL and 17‐AAG was 0.28 and 0.44 in A549 and H460 cells, respectively, indicative of strong synergistic activity. 17‐AAG increased the level of apoptosis by enhancing activation of the extrinsic/caspase‐8 apoptosis pathway. In H460 cells intrinsic‐mitochondrial dependent apoptosis was also slightly enhanced. Combined treatment resulted in cleavage of RIP1 and down‐regulation of Akt and ERK. Inhibition of Akt activity by LY294002 resulted in a significant increase in TRAIL‐induced apoptosis. In conclusion, we found that 17‐AAG enhances TRAIL‐induced apoptosis in NSCLC by stimulating the extrinsic apoptotic pathway, which could be linked to the suppression of Akt signaling. The combined use of Hsp90 targeting agents and induction of apoptosis by TRAIL receptor agonists might be of therapeutic value in the treatment of NSCLC. Key Words: TRAIL, 17‐AAG, HSP90, NSCLC, synergy, apoptosis ‐ 84 ‐
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Chapter 5<br />
Inhibition of Hsp90 by 17‐AAG enhances TRAIL‐induced<br />
apoptosis in non‐small cell lung cancer cells.<br />
Kaamar Azijli, Saravanan Yuvaraj, Sjors Kas, Godefridus J. Peters, Steven de<br />
Jong, Frank A.E. Kruyt<br />
Submitted <strong>for</strong> publication
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