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pH regulators and their inhibitors in tumor microenvironment
Senyi Liao1, Guang Wu2, Zhizhong Xie1
1Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
European Journal of Medicinal Chemistry
|February 3, 2024
Summary
The acidic tumor microenvironment (TME) fuels cancer progression and drug resistance. This review explores pH regulators like monocarboxylate transporters (MCTs) and carbonic anhydrase IX (CA IX) as targets for new antitumor drugs.
Area of Science:
- Oncology
- Biochemistry
- Cancer Biology
Background:
- The acidic tumor microenvironment (TME) is a hallmark of cancer, promoting immune escape, invasion, and metastasis.
- Tumor acidity arises from metabolic byproducts like lactic acid and CO2.
- Key pH regulators, including monocarboxylate transporters (MCTs), carbonic anhydrase IX (CA IX), and Na+/H+ exchange 1 (NHE1), maintain this acidic TME.
Purpose of the Study:
- To review the critical functions of pH regulators in establishing an acidic TME.
- To examine the structure-activity relationships of inhibitors targeting these pH regulators.
- To outline strategies for developing small-molecule antitumor inhibitors targeting pH regulators.
Main Methods:
- Literature review of pH regulators in TME.
- Analysis of structural and functional data for pH regulator inhibitors.
- Exploration of structure-activity relationships (SAR) for small-molecule inhibitors.
Main Results:
- pH regulators actively contribute to tumor acidity and associated malignant behaviors.
- Specific structural features of inhibitors correlate with their efficacy.
- Understanding SAR provides a basis for rational drug design.
Conclusions:
- Targeting pH regulators offers a promising therapeutic strategy against cancer.
- Small-molecule inhibitors targeting MCTs, CA IX, and NHE1 show potential for antitumor activity.
- Further research into inhibitor development could lead to novel cancer treatments.
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