Abstract
Autophagy contributes to the treatment-resistance of many types of cancers, and chloroquine (CQ) inhibits autophagy. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) kills cancer cells but is minimally cytotoxic to normal cells. However, because the therapeutic efficacy of TRAIL is limited, it is necessary to augment TRAIL-induced anti-tumor effects. In this study, we explored the anti-tumor effects of a combination of CQ and TRAIL on two human pancreatic cancer cell lines: TRAIL-sensitive MiaPaCa-2 cells and Panc-1 cells that are less sensitive to TRAIL. Although both CQ and TRAIL reduced cancer cell viability in a dose-dependent manner, the combination acted synergistically. CQ increased the expression level of type-II LC3B without decreasing the expression of p62, an autophagic substrate, thus indicating inhibition of autophagy. CQ did not increase the levels of death receptors on cancer cells but reduced the expression of anti-apoptotic proteins. A combination of CQ and TRAIL significantly increased cancer cell apoptosis. CQ induced cell-cycle arrest in the G2/M phase. Also, CQ increased the p21 level but reduced that of cyclin B1. A combination of CQ and TRAIL reduced the colony-forming abilities of cancer cells to extents greater than either material alone. In xenograft models, combination CQ and TRAIL therapy significantly suppressed the growth of subcutaneously established MiaPaCa-2 and Panc-1 cells, compared with the untreated or monotherapy groups. Together, the results indicate that CQ in combination with TRAIL may be useful to treat human pancreatic cancer.
Highlights
Autophagy has received a great deal of attention as a mechanism whereby cancer cells become resistant to therapy
Several reports have indicated that inhibition of autophagy increases the sensitivity of human cancer cells to the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) [9,10,11]. In support of this notion, we previously reported that pifithrin-μ, which inhibits both HSP70 and autophagy, enhanced the TRAIL-induced antitumor effects on human pancreatic cancer cells [12]
We investigated the effects of CQ, an inhibitor of autophagy, on the TRAIL-sensitivity of two human pancreatic cancer cell lines: the TRAIL sensitive MiaPaCa-2 line and the Panc-1 line that is less sensitive to TRAIL
Summary
Autophagy has received a great deal of attention as a mechanism whereby cancer cells become resistant to therapy. Autophagy plays a fundamental role in protecting cells under conditions of starvation and stress [1]. These functions can render cancer cells therapy-resistant [2, 3]. Effects of CQ and TRAIL on pancreatic cancer
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