TRAIL and agonistic
death receptor-specific
antibodies can induce apoptosis in
cancer cells with little cytotoxicity to normal cells. To improve TRAIL-induced antitumor effects, we tested its effectiveness in combination with
pifithrin (PFT)-μ, which has the potential to inhibit HSP70 function and autophagy, both of which participate in TRAIL resistance in
cancer cells. Among the four human
pancreatic cancer cell lines tested, MiaPaca-2, Panc-1, and BxPC-3 cells showed varying sensitivities to TRAIL. In MiaPaca-2 and Panc-1 cells, knockdown of HSP70 or
beclin-1, the latter an autophagy-related molecule, by RNA interference augmented TRAIL-induced antitumor effects, decreasing cell viability, and increasing apoptosis. On the basis of these findings, we next determined whether the TRAIL-induced antitumor effects could be augmented by its combination with PFT-μ. The combination of TRAIL plus PFT-μ significantly decreased the viability and colony-forming ability of MiaPaca-2 and Panc-1 cells compared with cells treated with either agent alone. When applied alone, PFT-μ increased
Annexin V(+) cells in both
caspase-dependent and -independent manners. It also promoted TRAIL-induced apoptosis and arrested
cancer cell growth. Furthermore, PFT-μ antagonized TRAIL-associated NF-κB activation in
cancer cells. In a xenograft mouse model, combination
therapy significantly inhibited MiaPaca-2
tumor growth compared with treatment with either agent alone. The results of this study suggest protective roles for HSP70 and autophagy in TRAIL resistance in
pancreatic cancer cells and suggest that PFT-μ is a promising agent for use in
therapies intended to enhance the antitumor effects of TRAIL.