Abstract
Pancreatic cancer (PC) is one of the most aggressive solid malignancies with poor treatment response and low survival rates. Herbal medicines such as betulinic acid (BA) have shown potential in treating various solid tumours, but with limitations that can be circumvented by polymer-drug conjugation. Polyethylene glycol-BA (PEG-BA) polymer-drug conjugate has previously shown selective anticancer activity against PC cells. Here, we elucidate the mechanism of cell death and the cell death pathway, anti-inflammatory and antioxidant activities of PEG-BA. PEG-BA induced apoptotic cell death by arresting MIA-PaCa-2 cells in the Sub-G1 phase of the cell cycle compared with BA and untreated cells (39.50 ± 5.32% > 19.63 ± 4.49% > 4.57 ± 0.82%). NFκB/p65 protein expression was moderately increased by PEG-BA (2.70 vs. 3.09 ± 0.42 ng/mL; p = 0.1521). However, significant (p < 0.05) overexpression of the proapoptotic genes TNF (23.72 ± 1.03) and CASPASE 3 (12,059.98 ± 1.74) compared with untreated cells was notable. The antioxidant potential of PEG-BA was greater (IC50 = 15.59 ± 0.64 µM) compared with ascorbic acid (25.58 ± 0.44 µM) and BA-only (>100 µM) and further confirmed with the improved reduction of hydroperoxide levels compared with BA-only (518.80 ± 25.53 µM vs. 542.43 ± 9.70 µM). In conclusion, PEG-BA activated both the intrinsic and extrinsic pathways of apoptosis and improved antioxidant activities in PC cells, suggesting enhanced anticancer activity upon conjugation.
Funder
National Research Foundation of South Africa
the University of the Witwatersrand Faculty Research Committee Individual
South African Medical Research Council
Subject
Polymers and Plastics,General Chemistry
Reference84 articles.
1. Cancer statistics, 2021;Siegel;CA Cancer J. Clin.,2021
2. Epidemiology and burden of pancreatic cancer;Maisonneuve;Presse Médicale,2019
3. Pancreatic cancer;Kleeff;Nat. Rev. Dis. Primer.,2016
4. Kim, A., Ha, J., Kim, J., Cho, Y., Ahn, J., Cheon, C., Kim, S., Ko, S., and Kim, B. (2021). Natural products for pancreatic cancer treatment: From traditional medicine to modern drug discovery. Nutrients., 13.
5. Betulinic acid and its derivatives: A review on their biological properties;Yogeeswari;Curr. Med. Chem.,2005
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