Article Impact Level: HIGH Data Quality: STRONG Summary of Cell Stem Cell. https://doi.org/10.1016/j.stem.2024.10.007 Dr. Chun Liu et al.
Points
- Doxorubicin, a chemotherapy drug, is limited by severe cardiovascular side effects, prompting the need for targeted therapies to mitigate its cardiotoxicity.
- Using iPSC-derived cardiomyocytes, CRISPR-based screens, and small-molecule assays, researchers identified carbonic anhydrase 12 (CA12) as a critical gene involved in DIC.
- Genetic inhibition of CA12 and using Indisulam, a CA12 antagonist, improved cell survival, sarcomere integrity, and calcium handling in cardiomyocytes, reducing DIC effects in both in vitro and animal models.
- Doxorubicin-induced upregulation of CA12 drives increased glycolysis, disrupting cardiomyocyte function and contributing to cardiotoxicity, which can be mitigated by CA12 inhibition.
- Targeting CA12 with inhibitors like Indisulam provides a promising strategy to alleviate DIC, paving the way for safer chemotherapy regimens without compromising doxorubicin’s anti-cancer efficacy.
Summary
Doxorubicin, a widely used chemotherapy drug, is limited by its life-threatening cardiovascular side effects, including doxorubicin-induced cardiotoxicity (DIC). To identify therapeutic targets for mitigating these effects, an integrated drug discovery pipeline was utilized, combining human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs), CRISPR interference and activation (CRISPRi/a) bidirectional pooled screens, and small-molecule screening. This approach identified several candidate genes linked to DIC, including carbonic anhydrase 12 (CA12).
Inhibition of CA12 significantly protects iCMs from DIC by improving cell survival, preserving sarcomere structural integrity, maintaining contractile function, and enhancing calcium handling. Specifically, the genetic inhibition of CA12 improved cellular responses to doxorubicin, demonstrating its crucial role in the cellular pathology of cardiotoxicity. Additionally, the small molecule inhibitor Indisulam, a CA12 antagonist, was shown to attenuate DIC in both iCMs and engineered heart tissue. In animal models, Indisulam also reduced the adverse effects of doxorubicin, confirming its potential as a therapeutic strategy.
Doxorubicin-induced upregulation of CA12 led to enhanced glycolysis in cardiomyocytes, which contributed to the dysfunction associated with DIC. This metabolic shift interfered with cellular functions, exacerbating the cardiotoxicity. These findings highlight CA12 as a promising target for drug development, offering a potential pathway to mitigate doxorubicin-induced cardiac damage without compromising its efficacy against cancer. The study lays the groundwork for future therapeutic strategies, aiming to reduce cardiovascular side effects while preserving the anti-cancer activity of doxorubicin.
Link to the article: https://www.sciencedirect.com/science/article/abs/pii/S1934590924003692
References Liu, C., Shen, M., Liu, Y., Manhas, A., Zhao, S. R., Zhang, M., Belbachir, N., Ren, L., Zhang, J. Z., Caudal, A., Nishiga, M., Thomas, D., Zhang, A., Yang, H., Zhou, Y., Ameen, M., Sayed, N., Rhee, J.-W., Qi, L. S., & Wu, J. C. (2024). CRISPRi/a screens in human iPSC-cardiomyocytes identify glycolytic activation as a druggable target for doxorubicin-induced cardiotoxicity. Cell Stem Cell. https://doi.org/10.1016/j.stem.2024.10.007
