Pimavanserin: A novel autophagic regulator for pancreatic cancer treatment

다국어 초록 (Multilingual Abstract)

Pancreatic cancer patients have limited treatment options in spite of several advanced treatment strategies. Pancreatic tumors exhibit high basal autophagy compared to other cancers. Several studies including from our lab reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we have demonstrated that pimavanserin (PVT) suppresses pancreatic tumor growth by inducing autophagy‐mediated apoptosis. Our results indicated that PVT induced 1.8 – 5 fold autophagy in pancreatic ductal adenocarcinoma (PDAC) cells, as evaluated by increased acridine orange staining. Furthermore, accumulation of double membrane vesicles (autophagosomes) and formation autophagolysosomes were observed with PVT treatment. Genomic analysis by R2 & GEPIA database revealed that PDAC patients exhibited reduced levels of autophagy initiator gene, ULK1. PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin‐1, Atg5, and LC3A/B in several pancreatic cancer cells. In addition, phosphorylation of ULK1 at Ser757 was inhibited with PVT treatment. Apoptotic effects of PVT in pancreatic cancer cells was validated by increase in cleavage of caspase3. ULK1 agonist LYN‐1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in pancreatic cancer cells. Our in vivo findings demonstrated that chloroquine abrogated the growth suppressive effects of PVT by 21% in sub‐cutaneously implanted BxPC3 tumor xenografts. Moreover, chloroquine reduced the effects of PVT in inducing the expression of ULK1 and the cleavage of caspase 3 as evaluated by western blotting. Oral administration of PVT suppressed BxPC3 tumor xenografts by 50% in athymic nude mice. In another in vivo experiment, PVT treatment inhibited the growth of orthotopicaly implanted PANC1 tumors by 77%. Chronic administration of PVT did not exhibit any general signs of toxicity or behavioral side effects in mice. Moreover, long‐term administration of PVT did not altered the clinical chemistry parameters like ALT, AST, total serum protein, calcium, creatinine, BUN and albumin. Collectively, our results indicate that PVT mediated pancreatic tumor growth suppression was associated with induction of autophagy mediated apoptosis. Since, PVT is already available in clinic with an established safety profile, our results will accelerate its clinical development for pancreatic cancer therapy.