Animesh Dhar
Kansas University Medical Center, USA
Title: Novel Combination of Natural Compounds GZ17-6.02 Inhibits Tumorigenesis in Pancreatic Cancer by Suppressing SHH Signaling
Biography
Biography: Animesh Dhar
Abstract
Background: Novel therapeutic targets are needed to treat pancreatic cancer because nothing is available for this devastating disease. GZ17-06.02, combination of novel natural compounds, contains anti-cancer properties in several cancers. Therefore, we hypothesize that GZ17-06.02 will inhibit tumor progression and metastasis in PDAC by suppressing cancer stem cells (CSC) and sonic hedgehog (SHH) pathway.
Methods: We have determined cell proliferation, pancosphere formation and apoptosis following treatment of different doses GZ17-6.02 in human pancreatic cancer cells. Orthotopic pancreatic cancer model in athymic nude mice was developed and GZ17-6.02 was given orally for 20 days. Proliferative markers, pEGFR/pAkt and apoptotic markers, Bax- Bcl-2- Caspase3 and also metastatic markers, MMP-2 and MMP-9 were measured in primary and metastatic tumor tissues. SHH pathway was determined using western blot, immunohistochemistry and cellular thermal shift assay (CETSA). Bioavailability through oral delivery of GZ17-6.02 in mice demonstrated rapid clearance from circulation and showed significant absorption and distributed quickly in different tissues.
Results: GZ17-6.02 inhibits proliferation of pancreatic cancer cells in a dose and time-dependent manner. GZ17-6.02 induced apoptosis in both in vitro and in vivo pancreatic cancer. GZ17-6.02 significantly inhibited EGFR and Akt phosphorylation. Furthermore, GZ17-6.02 decreased the number and size of the pancospheres and inhibited CSCs markers such as DCLK1, Lgr5, EpCAM and Sox9. GZ17-6.02 inhibited SHH and the downstream signaling pathway including SUFU, Gli1 and Gli2. Significant interaction of GZ17-6.02 with SHH was found using CETSA assay. Metastatic markers, MMP-2 and MMP-9 activity increased in the tumors. GZ17-6.02 treatment down-regulation of proliferative and anti-apoptotic genes using RNAseq data. GZ17-6.02 has also been detected in different tissues particularly in liver when it is given orally.
Conclusion: GZ17-6.02 significantly reduces tumorigenesis and metastasis in both in vitro and in vivo pancreatic cancer models through impairment of CSCs and SHH pathway.