VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study

Abstract

The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic drugs from cancer cells, thereby producing MDR. Our research efforts have led to the discovery of VKNG-1, a compound that selectively inhibits the ABCG2 transporter and reverses resistanctabe to standard anticancer drugs both in vitro and in vivo. VKNG-1, at 6 µM, selectively inhibited ABCG2 transporter and sensitized ABCG2-overexpressing drug-resistant cancer cells to the ABCG2 substrate anticancer drugs mitoxantrone, SN-38, and doxorubicin in ABCG2-overexpressing colon cancers. VKNG- 1 reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the mRNA and protein levels. Moreover, VKNG-1 inhibits the level of phosphorylated protein kinase B (PKB/p-AKT), and B-cell lymphoma-2 (Bcl-2) protein which may overcome resistance to anticancer drugs. However, the in vitro translocation of ABCG2 protein did not occur in the presence of 6 µM of VKNG-1. In addition, VKNG-1 enhanced the anticancer efficacy of irinotecan in ABCG2- overexpressing mouse tumor xenografts. Overall, our results suggest that VKNG-1 may, in combination with certain anticancer drugs, represent a treatment to overcome ABCG2-mediated MDR colon cancers.

Lycium barbarum polysaccharide reverses drug resistance in oxaliplatin-resistant colon cancer cells by inhibiting PI3K/AKT-dependent phosphomannose isomerase

“…The results of the KEGG pathway enrichment analysis mainly involved cancer-related signaling pathways, PI3K-Akt signaling pathway, cancer microRNAs, progesterone-mediated follicle maturation pathway, insulin resistance pathway, cellular senescence signaling pathway, bladder cancer signaling pathway, IL-17 signaling pathways, axon guidance signaling pathway, and gonadotropin-releasing hormone signaling pathway. The AKT protein family plays an important role in the functionality of the ABC family of drug-resistance proteins ( Lu et al, 2020 ; Narayanan et al, 2021 ). The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR promises to improve current strategies based on combined drug treatments to overcome MDR challenges ( Zhang L. et al, 2020 ).…”

The AKT inhibitor, MK-2206, attenuates ABCG2-mediated drug resistance in lung and colon cancer cells

“…The ATPase activity of vanadate-sensitive ABCG2 was determined as previously described ( Ji et al, 2018 ; Yang et al, 2020b ; Narayanan et al, 2021a ). High Five insect cells was used to prepare ABCG2 membrane vesicles.…”

Anticancer effect of Indanone-based thiazolyl hydrazone derivative on p53 mutant colorectal cancer cell lines: An in vitro and in vivo study

“…The CRC cells, HT-29, and KM 12 xenograft mouse models were established as previously reported ( 36 , 37 ). The HT-29 (6 × 10 6) and KM 12 cells (7 × 10 6 ) were implanted into the mice (right and left sides, respectively), and when the tumors attained a diameter of around 0.5 cm (day 0) after one week, the animals were divided into four groups of six each as follows: (a) polyethylene glycol 300 as the vehicle, given orally (q3d × 7); (b) irinotecan (30 mg/kg, q3d × 7), given intraperitoneally (i.p.…”