2’, 3’-Dehydrosalannol: A Potent Anticancer Agent for Pancreatic Ductal Carcinoma
Introduction
Pancreatic ductal carcinoma (PDAC) is a highly aggressive form of pancreatic cancer, known for its late-stage diagnosis and limited treatment options. Therefore, it is essential to identify an effective and safe therapeutic drug to treat patients with PDAC. In this study, we investigated the chemo-preventive and chemo-therapeutic effects of 2’-3’ Dehydrosalannol (DHS) a derivative from Azadirachta indica on PDAC.
Methods
We used pancreatic cancer cell lines HPAC, MIAPACA-2, ASPC-1, and normal pancreas cell line hTERT HPNE for this study. These cells were treated with varying concentrations of 2’-3’ Dehydrosalannol (DHS)to assess cell viability using MTS assay. To evaluate the metastatic effects of DHS colony formation, matrigel invasion, and transwell migration, scratch assays were performed. We analyzed the expression of key molecular markers associated with cell proliferation, metastasis, and apoptosis, in the presence of DHS. Apoptosis was assessed using annexin V/PI staining to determine the effects of DHS on programmed cell death. Nude mice were utilized to establish an in vivo xenograft model of pancreatic cancer. HPAC cells were implanted subcutaneously into the mice at a concentration of 1.5x106 cells/flank. In chemotherapeutic experimental studies, DHS was then administered (1.0 and 2.5 mg/kg bw) intraperitoneallybiweekly for four weeks after the tumors reached 100mm3. In another group, DHS was administered two weeks prior to the tumor transplant to investigate the chemo-preventive effects. Xenograft tumorgrowth was monitored weekly. Expression levels of proliferative, EMT and apoptotic markers were analyzed using immune blot and immunohistochemistry.
Results
Our findings demonstrate that DHS effectively reduces cell viability, colony formation, invasion, and migration of PDAC cells. Interestingly, treatment with DHS did not cause any significant antiproliferative effect in normal pancreatic cells (hTERT HPNE) compared to PDAC cells. Furthermore, it downregulated key signaling markers associated with proliferation (pAKT, pPI3K, pmTOR, Ki67, etc), metastasis (E-cad, N-cad, Slug, Snail, Vimentin and Gli1), and induces apoptosis (Bax, BCL2, and Caspases 3, 8, 9, PARP). In vivo data demonstrated that DHS is an effective chemo-preventive and therapeutic drug. Both dosage groups (1.0 mg/kg bw and 2.5 mg/kg bw) of DHS effectively inhibited the growth of PDAC tumor xenografts.
Conclusion
These results highlight the potential of DHS as a promising anticancer agent against PDAC.