AZ32 Reverses ABCG2-Mediated Multidrug Resistance in Colorectal Cancer

Colorectal cancer is a common malignancy with the third highest incidence and second highest mortality rate among all cancers in the world. Chemotherapy resistance in colorectal cancer is an essential factor leading to the high mortality rate. The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) confers multidrug resistance (MDR) to a range of chemotherapeutic agents by decreasing their intracellular content. The development of novel ABCG2 inhibitors has emerged as a tractable strategy to circumvent drug resistance. In this study, an ABCG2-knockout colorectal cancer cell line was established to assist inhibitor screening. Additionally, we found that ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 could sensitize ABCG2-overexpressing colorectal cancer cells to ABCG2 substrate chemotherapeutic drugs mitoxantrone and doxorubicin by retaining them inside cells. Western blot assay showed that AZ32 did not alter the expression of ABCG2. Moreover, molecule docking analysis predicted that AZ32 stably located in the transmembrane domain of ABCG2. In conclusion, our result demonstrated that AZ32 could potently reverse ABCG2-mediated MDR in colorectal cancer.

 

Comments:

Thank you for sharing the information about the study on colorectal cancer and ABCG2-mediated multidrug resistance (MDR). It appears that the study aimed to address the issue of chemotherapy resistance in colorectal cancer by focusing on the ATP-binding cassette (ABC) superfamily G member 2 (ABCG2).

Here's a summary of the key points from the information you provided:

1. **Background on Colorectal Cancer:**
   - Colorectal cancer is a prevalent malignancy, ranking third in incidence and second in mortality among all cancers globally.

2. **Role of ABCG2 in Chemotherapy Resistance:**
   - ABCG2, a member of the ABC superfamily, is implicated in multidrug resistance (MDR) in colorectal cancer.
   - ABCG2 reduces the intracellular content of chemotherapeutic agents, contributing to chemotherapy resistance.

3. **Study Approach:**
   - The study established an ABCG2-knockout colorectal cancer cell line to facilitate the screening of ABCG2 inhibitors.

4. **Identification of a Potential Inhibitor - AZ32:**
   - The ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 was identified as a potential inhibitor.
   - AZ32 was found to sensitize ABCG2-overexpressing colorectal cancer cells to chemotherapeutic drugs (mitoxantrone and doxorubicin) by retaining them inside cells.

5. **Mechanism of Action:**
   - Western blot assay results indicated that AZ32 did not alter the expression of ABCG2.
   - Molecular docking analysis predicted that AZ32 stably located in the transmembrane domain of ABCG2.

6. **Conclusion:**
   - The study concludes that AZ32 could effectively reverse ABCG2-mediated multidrug resistance in colorectal cancer.

This research suggests that ATM kinase inhibitor AZ32 may have potential therapeutic implications in overcoming chemotherapy resistance in colorectal cancer by modulating ABCG2-mediated drug efflux. Further research and clinical trials would be needed to validate these findings and assess the translational relevance of AZ32 as a potential treatment strategy for colorectal cancer.

Related Products

Cat.No.	Product Name	Information
S8729	AZ32	AZ32 is a specific inhibitor of the ATM kinase that possesses good BBB penetration in mouse with an IC50 value of <0.0062 μM for ATM enzyme. It shows adequate selectivity over ATR and also has high cell permeability.

Related Targets

ATM/ATR