Dorsomorphin attenuates ABCG2-mediated multidrug resistance in colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Colorectal cancer (CRC) presents a significant global health challenge, characterized by high mortality rates.
• Chemotherapy resistance, particularly multidrug resistance (MDR), is a primary driver of treatment failure in CRC.
• Overexpression of the ABCG2 transporter in cancer cells leads to the efflux of chemotherapeutic agents, contributing to MDR.

Purpose of the Study:

• To investigate the potential of dorsomorphin as an inhibitor of ABCG2 transporter activity.
• To evaluate the efficacy of dorsomorphin in overcoming ABCG2-mediated multidrug resistance in colorectal cancer cells.
• To elucidate the mechanism by which dorsomorphin interacts with ABCG2.

Main Methods:

• Cell-based assays were used to assess the effect of dorsomorphin on ABCG2 transporter activity.
• The impact of dorsomorphin on the intracellular accumulation of chemotherapeutic agents (mitoxantrone, doxorubicin) was evaluated.
• Molecular docking studies were performed to predict the binding interaction between dorsomorphin and the ABCG2 protein.

Main Results:

• Dorsomorphin potently inhibited the transporter activity of ABCG2.
• Dorsomorphin treatment led to increased intracellular concentrations of mitoxantrone and doxorubicin in ABCG2-overexpressing colorectal cancer cells.
• Molecular docking revealed stable binding of dorsomorphin within the ABCG2-binding pocket, suggesting a direct inhibitory mechanism.
• Dorsomorphin did not affect the overall protein expression levels of ABCG2.

Conclusions:

• Dorsomorphin acts as a potent inhibitor of ABCG2 transporter function.
• By inhibiting ABCG2, dorsomorphin can restore the sensitivity of colorectal cancer cells to standard chemotherapeutic agents.
• Dorsomorphin represents a promising therapeutic strategy to combat ABCG2-mediated multidrug resistance in colorectal cancer.