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

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 (SW480^R) 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.

Annonacin; Colon cancer; Multidrug resistance; Oxaliplatin; P-gp.