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

• Published in: Environmental toxicology and pharmacology Vol. 68; pp. 120 - 132
• Main Authors: Chowdhury, Kaustav Dutta, Sarkar, Avik, Chatterjee, Sujan, Patra, Debajyoti, Sengupta, Dipanwita, Banerjee, Soumi, Chakraborty, Pratip, Sadhukhan, Gobinda Chandra
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2019; Elsevier Science Ltd
• Subjects: Andrographolide; Antineoplastic drugs; Antitumor agents; Apoptosis; Apoptosis-inducing factor; Cascades; Caspase; Cathepsin B; cathepsinB; Cell activation; Cell cycle; Chemoresistance; Cisplatin; Cyclin A; Cytotoxicity; Hepatocellular carcinoma; HepG2; IKK protein; Kinases; Liver cancer; Localization; Phosphatidylserine; PP2A; Protein kinase A; Protein phosphatase; Proteins; Scramblase; Toxicity; Iκβ; Cisp; cFLIP; PKA; IKK; HepG2CR; HCC; PP2A; cAMP; Cisplatin; Andro; PEN-STREP; FBS; HepG2; cathepsinB; Scramblase; Andrographolide; AIF
• ISSN: 1382-6689; 1872-7077; 1872-7077
• DOI: 10.1016/j.etap.2019.03.003

•40 μM andrographolide after 48 h reduces 50% HepG2CR cell survivability.•Andrographolide significantly up-regulates PKA/PP2 A/IKK axis.•Event initiates cathepsinB-tAIF-scramblase mediated ‘eat me’ signal in HepG2CR.•Cyclin A and B downregulation and increase in pTyr15CDK1 result subG1 phase arrest.•No additive/synergistic andrographolide effects with cisplatin against resistance. Andrographolide 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.