Cathepsin B mediated scramblase activation triggers cytotoxicity and cell cycle arrest by andrographolide to overcome cellular resistance in cisplatin resistant human hepatocellular carcinoma HepG2 cells

Publication date: Available online 5 March 2019Source: Environmental Toxicology and PharmacologyAuthor(s): Kaustav Dutta Chowdhury, Avik Sarkar, Sujan Chatterjee, Debajyoti Patra, Dipanwita Sengupta, Soumi Banerjee, Pratip Chakraborty, Gobinda Chandra SadhukhanAbstractAndrographolide regimen in single or in combination with anticancer drugs is a promising new strategy to reverse chemoresistance in heaptocellular carcinoma. Apoptosis inducing factor (AIF) may regulate a complementary, cooperative or redundant pathway, along with caspase cascades. Despite these findings, mechanisms underlying caspase-dependent and-independent signaling pathways in andrographolide -induced apoptosis in cisplatin-resistant human hepatocellular carcinoma cell line (HepG2CR) remain unclear. Andrographolide treatment effectively reduced NF-κβ nuclear localization by modulating protein kinase A- protein phosphatase 2 A- Iκβ kinase (PKA/PP2 A/IKK) axis that in turn maintains initiator caspase8 activity. Lysosomal distribution of tBid stimulates cytosolic cathepsin B resulting accumulation of truncated-AIF with induction in scramblase mediated phosphatidylserine exposure in HepG2CR cells. Andrographolide treatment thereby switch on subG1 phase arrest by modulating cellular check points (cyclin A, B, cyclin dependent kinase-1) cueing to the apoptosis event. Collectively, this study suggested antineoplastic potential of andrographolide through PKA/PP2 A/IKK pathway in HepG2CR cells.
Source: Environmental Toxicology and Pharmacology - Category: Environmental Health Source Type: research