Overcoming multi drug resistance mediated by ABC transporters by a novel acetogenin- annonacin from Annona muricata L

by Selleckchem | Feb 03 2024

Ethnopharmacological relevance: Multi-Drug Resistance (MDR), mediated by P-glycoprotein (P-gp) is one of the barriers to successful chemotherapy in colon cancer patients. Annona muricata L. (A.muricata), commonly known as soursop/Graviola, is a medicinal plant that has been traditionally used in treating diverse diseases including cancer. Phytochemicals of A.muricata (Annonaceous Acetogenins-AGEs) have been well-reported for their anti-cancer effects on various cancers.

Aim of the study: The study aimed to examine the effect of AGEs in reversing MDR in colorectal cancer cells.

Methods: Based on molecular docking and molecular dynamic simulation, the stability of annonacin upon P-gp was investigated. Further in vitro studies were carried in oxaliplatin-resistant human colon cancer cells (SW480R) to study the biological effect of annonacin, in reversing drug resistance in these cells.

Results: Molecular docking and simulation studies have indicated that annonacin stably interacted at the drug binding site of P-gp. In vitro analysis showed that annonacin was able to significantly reduce the expression of P-gp by 2.56 folds. It also induced apoptosis in the drug-resistant colon cancer cells. Moreover, the intracellular accumulation of P-gp substrate (calcein-AM) was observed to increase in resistant cells upon treatment with annonacin.

Conclusion: Our findings suggest that annonacin could inhibit the efflux of chemotherapeutic drugs mediated by P-gp and thereby help in reversing MDR in colon cancer cells. Further in vivo studies are required to decipher the underlying mechanism of annonacin in treating MDR cancers.

Comments:

That's an intriguing study! It seems like the research on Annona muricata's compounds, specifically Annonaceous Acetogenins (AGEs), showcases promising potential in addressing Multi-Drug Resistance (MDR) in colorectal cancer.

The use of molecular docking and simulation techniques to assess the interaction between annonacin and P-glycoprotein (P-gp) and then validating it with in vitro studies on oxaliplatin-resistant colon cancer cells (SW480R) is a robust approach. The observed reduction in P-gp expression, induction of apoptosis, and increased intracellular accumulation of P-gp substrate upon annonacin treatment in drug-resistant cells are significant findings. These results suggest that annonacin could potentially inhibit the efflux of chemotherapeutic drugs mediated by P-gp, thus aiding in overcoming MDR in colon cancer cells.

However, as the conclusion suggests, further in vivo studies are essential to delve deeper into the mechanisms underlying annonacin's action in treating MDR cancers. Such studies could provide valuable insights into the efficacy, safety, and potential clinical applications of annonacin as a therapeutic agent for combating drug resistance in colorectal cancer.

This research presents a promising avenue for the development of novel strategies to address drug resistance, potentially improving the effectiveness of chemotherapy in treating colorectal cancer.