towards improved death receptor targeted therapy for ... - TI Pharma

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
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