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Updated: May 23, 2025
Detection of Mitochondria Membrane Potential to Study CLIC4 Knockdown-induced HN4 Cell Apoptosis In Vitro
Published on: July 17, 2018
The mitochondrial protease ClpP is a promising target for multiple myeloma treatment
Xiang Liu1, Jinlong Gu2, Song Liu2
1Department of Hematology/Institute of Hematology, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
Drug resistance and relapse are the major obstacles in multiple myeloma (MM) treatment, driving the search for novel therapeutics. The chemoactivation of mitochondrial caseinolytic protease P (ClpP) has shown to have anticancer effects on many tumors, but has seldom been elucidated in MM. Here we found that the CLPP expression was elevated in MM patients, and further increased in relapsed cases. After synthesizing and screening a panel of ClpP agonists, we identified a compound, 7b, as the most potent anti-MM agent in vitro. 7b activated ClpP protease activity, selectively degrading mitochondrial proteins, many of which are involved in oxidative phosphorylation (OXPHOS). As result, 7b treated MM had metabolic dysfunction, the mitochondrial membrane potential (MMP) collapse, reduced OXPHOS levels, and increased mitochondrial reactive oxygen species (ROS), leading to mitophagy-mediated MM cell death. Notably, 7b also showed efficacy against drug-resistant MM cell lines, including bortezomib- and lenalidomide-resistant cells. In vivo, 7b also exhibited remarkable anti-MM activity with tolerable side effects. In conclusion, targeting ClpP represents a promising therapeutic strategy for MM, with 7b serving as a potent anti-MM agent, especially for relapsed and refractory MM.
Insights
A novel compound, 7b, targets mitochondrial caseinolytic protease P (ClpP) to effectively kill multiple myeloma (MM) cells, including drug-resistant types. This ClpP activation offers a promising therapeutic strategy for relapsed and refractory MM.
Area of Science:
- Molecular Biology
- Cancer Therapeutics
- Mitochondrial Biology
Background:
- Drug resistance and relapse are significant challenges in multiple myeloma (MM) treatment, necessitating new therapeutic approaches.
- Mitochondrial caseinolytic protease P (ClpP) activation has shown anticancer potential in various tumors, but its role in MM is underexplored.
Purpose of the Study:
- To investigate the role of ClpP in MM and evaluate novel ClpP agonists as potential anti-MM agents.
- To identify and characterize a potent ClpP activator for treating drug-resistant and relapsed multiple myeloma.
Main Methods:
- Synthesis and screening of ClpP agonists to identify potent anti-MM compounds.
- In vitro assessment of compound 7b's effects on MM cells, including ClpP activation, mitochondrial function, and cell death pathways.
- Evaluation of compound 7b's efficacy in drug-resistant MM cell lines and in vivo mouse models.
Main Results:
- ClpP expression is elevated in MM patients, particularly in relapsed cases.
- Compound 7b potently activated ClpP, leading to mitochondrial protein degradation, impaired oxidative phosphorylation (OXPHOS), mitochondrial membrane potential (MMP) collapse, and increased reactive oxygen species (ROS).
- 7b induced mitophagy-mediated MM cell death and demonstrated efficacy against bortezomib- and lenalidomide-resistant MM cells, with good tolerability in vivo.
Conclusions:
- Targeting ClpP is a promising therapeutic strategy for multiple myeloma.
- Compound 7b is a potent ClpP activator with significant anti-MM activity, especially effective against relapsed and refractory disease.
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