Semisynthetic derivatives of andrographolide inhibit growth of pancreatic cancer cells via induction of G1 phase cell cycle arrest and apoptosis
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1
Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia
Background
Pancreatic ductal adenocarcinoma, is currently the fourth leading cause of cancer death globally due to poor prognosis and late diagnosis. Mutation of Kirsten-Ras (K-Ras) oncogene is prevalent in pancreatic cancer patient as more than 90% of patients inherit it. Andrographolide (AGP) and its benzylidene derivatives were found to bind to K-Ras transient pockets resulting in inhibition of K-Ras-MAPK oncogenic signaling. In the current investigation, growth inhibition, cell cycle arrest and apoptosis inducing potential of semisynthetic benzylidene derivatives of AGP, namely 3,19-(2-bromobenzylidene) andrographolide (SRJ09), 3,19-(3-chloro-4-fluorobenzylidene) andrographolide (SRJ23) and 3,19-(2-bromobenzylidene)-14-acetylandrographolide (SRS07) were evaluated in Capan-2 (K-Ras G12V mutation) and PANC-1 (K-Ras G12D mutation) pancreatic cancer cell lines.
Methods
In vitro cytotoxic activity of AGP derivatives was assessed at 96 hours using MTT cell viability assay. Non-treated and treated cells were fixed in 70% ethanol and stained with propidium iodide before being subjected to quantification of cellular DNA content at different cell cycle stages by BD FACSCANTO II. Annexin V in combination with 7-Aminoactinomycin D (7-AAD) dye were used to stain cells, followed by analysis using Muse Cell Analyser that utilise fluorescent detection to detect phosphatidylserine (PS) on the surface of apoptotic cells.
Results
All three AGP derivatives were equally potent in Capan-2 and PANC-1 cells with IC50 values ranging from 3.2 µM to 4.9 µM. Cell cycle analysis showed that AGP analogue induced cell cycle arrest in G1 phase. Apoptosis assay revealed a decrease in viable cells, with concomitant increase in early and late apoptotic cells within 48 hours of exposure to AGP analogue.
Conclusion
The benzylidene derivatives of AGP inhibited growth of pancreatic cancer cells by inducing G1 phase cell cycle arrest and apoptosis.
Keywords:
Cell Cycle,
Apoptosis,
MTT assay,
Pancreatic Cancer,
andrographolide
Conference:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019.
Presentation Type:
Poster Presentation
Topic:
Cancer
Citation:
Revindran
S and
Stanslas
J
(2019). Semisynthetic derivatives of andrographolide inhibit growth of pancreatic cancer cells via induction of G1 phase cell cycle arrest and apoptosis.
Front. Pharmacol.
Conference Abstract:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”.
doi: 10.3389/conf.fphar.2018.63.00127
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Received:
30 Sep 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
Prof. Johnson Stanslas, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia, rcxjs@upm.edu.my