Abstract
Quinacrine has been identified as a potent DR5-inducing agent that sensitizes cancer cells to TRAIL-induced apoptosis. In the current study, we found that quinacrine increased DR5 mRNA levels significantly in ovarian cancer cell lines regardless of p53 status. Further study showed the half-life of DR5 in quinacrine-treated cells was significantly prolonged, indicating that DR5 protein degradation was inhibited by quinacrine. We tested if the combination of TRAIL and quinacrine could be effective in ovarian cancer treatment in vitro and in ovarian cancer xenograft mouse models. We found that quinacrine enhanced TRAIL sensitivity or reversed TRAIL resistance in all the ovarian cancer cell lines tested. Mice treated with quinacrine and TRAIL remained disease-free for up to 20 weeks, however, mice treated with TRAIL or quinacrine alone and in control group died within ~8 weeks after treatment. Intraperitoneal delivery of quinacrine and TRAIL is rational and practical with extraordinary synergistic anti-cancer effects in preclinical models of ovarian cancer. Clinical investigation of combining quinacrine with TRAIL for ovarian cancer treatment is warranted.
Highlights
The extrinsic apoptotic pathway has been well-investigated and characterized; targeting this pathway for cancer treatment has not been successful [1, 2]
While searching for small molecules targeting p53 [16,17,18], we identified a category of small molecules including quinacrine that induced substantial high levels of DR5 and enhanced TRAIL sensitivity or reversed TRAIL resistance in almost all cancer cell lines tested [16, 17, 19]
We demonstrated that quinacrine induced high level of DR5 and reversed TRAIL resistance in human ovarian cancer cell lines
Summary
The extrinsic apoptotic pathway has been well-investigated and characterized; targeting this pathway for cancer treatment has not been successful [1, 2]. The death receptor ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) appears to be an ideal cancer therapeutic with minimal toxicity in preclinical models. It can induce cell death in cancer cells but not normal cells [3,4,5]. Further clinical studies on various human cancers in combination with different standard chemotherapy regimens showed no remarkable synergistic anti-cancer effects [7,8,9], and in a trial for treatment of non-small cell lung cancer, TRAIL plus chemotherapy only moderately prolonged progression free survival (PFS) [10]. Due to limited clinical benefit, clinical trials using recombinant human TRAIL, as well as agonist antibodies to DR4 and DR5 (death receptors) were suspended
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