ABCB1 overexpression

These findings suggest that factors beyond gene expression, such as spheroid architecture, cell-cell interactions, and drug penetration, contribute to the enhanced resistance observed in 3D cultures. These results highlight the importance of 3D cell culture models for a more accurate representation of tumour drug resistance mechanisms in ovarian cancer, providing valuable insights for therapeutic development.

The present study proves that falnidamol acts as a highly potent and specific active ABCB1 transporter inhibitor, and can reverse ABCB1-mediated MDR, implying that combining falnidamol with ABCB1 substrate chemotherapeutic agents has the potential to overcome ABCB1-mediated MDR.

These findings highlight RK2 and RK3 as promising candidates for next stages of drug development. Their distinct mechanisms of action could lead to therapeutic solutions for MDR-related cancers, specifically linked to ABCB1 overexpression.

Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.

KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3...Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells...Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206)...These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations. Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells.

In this investigation, the treatment with solasodine and doxorubicin combination showed a notable increase in intracellular ROS generation in KBChR-8-5 cells...Additionally, the combination therapy increased the lipid peroxidation levels while simultaneously reducing the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and the levels of glutathione (GSH). These results demonstrated that solasodine disrupts redox balance, and overcomes drug resistance by downregulating P-gp via regulating Nrf2/Keap1 signaling pathway in MDR cancer cells.

These potent MDR1 inhibitors were found to enhance chemosensitivity to doxorubicin in MDR1-overexpressing cells...Furthermore, the total number of methoxy groups in the flavonol backbone was found to be a significant factor in determining the potency of MDR1 inhibition. These observations provide fundamental insights into the structure-activity relationship between flavonol derivatives and MDR1 inhibition, potentially aiding in overcoming drug resistance in cancer.

In the tumor-bearing mouse model, mobocertinib boosted the antitumor effect of paclitaxel and topotecan, resulting in tumor regression. In summary, our study uncovers a novel potential for repurposing mobocertinib as a dual inhibitor of ABCB1 and ABCG2, and suggests the combination of mobocertinib with substrate drugs as a strategy to counteract MDR.

In vivo studies have shown that gilteritinib improves the antitumor efficacy of paclitaxel in nude mice without obvious toxic effects. In conclusion, our preclinical investigations show that gilteritinib has the potential to successfully overcome ABCB1-mediated MDR in a clinical environment when combined with substrate medicines.

Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

In parallel, this dual ABCB1/CYP1B1 inhibitory effect drives compound A10 exhibiting prominent drug resistance reversal activity to doxorubicin (IC50 = 4.7 μM, RF = 13.7) in ABCB1/CYP1B1-overexpressing DOX-SW620/AD300-1B1 resistant cells, which is more potent than that of the CYP1B1 inhibitor ANF. Furthermore, although compound A2 possessed moderate ABCB1/CYP1B1 inhibitory activity, it showed considerable antiproliferative activity towards drug-resistant SW620/AD300 and MKN45-DDP-R cells, which may be partly related to the increase of PUMA expression to promote the apoptosis of the drug-resistant MKN45-DDP-R cells as confirmed by proteomics and western blot assay. These results indicated that the tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates may provide a fundamental scaffold reference for further discovery of MDR reversal agents.

In summary, our study demonstrates an additional pharmacological capability of epertinib against the activity of ABCB1 and ABCG2. These findings suggest that incorporating epertinib into combination therapy could be advantageous for a specific patient subset with tumors exhibiting high levels of ABCB1 or ABCG2, warranting further exploration.