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Updated: Jan 30, 2026
Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
Trichostatin A modulates cellular metabolism in renal cell carcinoma to enhance sunitinib sensitivity
Hiromi Sato1, Miaki Uzu2, Tatsuro Kashiba1
1Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
Abstract:
Although sunitinib is the first-line drug for progressive renal cell carcinoma (RCC), most patients experience its tolerance. One possible way of overcoming drug resistance is combination therapy. Epigenetic modifier is one of the candidate drug group. A recent evidence suggests that cell metabolism is regulated by epigenetic mechanisms. Epigenetic abnormalities lead to changes in metabolism and may contribute to drug resistance and progression of RCC. Consequently, we investigated whether trichostatin A (TSA), a potent histone-deacetylase (HDAC) inhibitor, alters sunitinib-induced cytotoxicity and metabolism in RCC cells at epigenetic regulatory concentrations. Combined metabolome and transcriptome analysis suggested that TSA impacts on energy productive metabolic pathways, such as those involving TCA cycle and nucleotide metabolism especially for increase of hyperphosphorylated form. Combination of sunitinib and TSA increased cell death with PARP cleavage, an early marker of mitochondrial apoptosis, whereas receptor tyrosine kinase signaling, which is the target of sunitinib, was not altered by TSA. Finally, the established sunitinib resistant-RCC cell (786-O Res) was also exposed to sunitinib and TSA combination, resulting in significant growth inhibition. In summary, it was suggested that TSA reduces sunitinib resistance by triggering intracellular metabolome shifts regarding energy metabolism, that is the first recognized mechanism as an HDAC inhibitor.
Insights
Trichostatin A (TSA), a histone deacetylase inhibitor, enhances sunitinib efficacy in renal cell carcinoma (RCC) by altering cell metabolism. This combination therapy overcomes sunitinib resistance and promotes cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Sunitinib is a first-line treatment for advanced renal cell carcinoma (RCC), but drug resistance is a significant clinical challenge.
- Epigenetic modifications, including those affecting cell metabolism, are implicated in RCC progression and drug resistance.
Purpose of the Study:
- To investigate the effects of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on sunitinib-induced cytotoxicity and metabolism in RCC cells.
- To explore the potential of TSA as a combination therapy to overcome sunitinib resistance in RCC.
Main Methods:
- Combined metabolome and transcriptome analysis of RCC cells treated with sunitinib and TSA.
- Assessment of cell death markers (e.g., PARP cleavage) and receptor tyrosine kinase signaling.
- Evaluation of the combination therapy in a sunitinib-resistant RCC cell line (786-O Res).
Main Results:
- TSA alters cellular metabolism, particularly energy-productive pathways like the TCA cycle and nucleotide metabolism.
- The combination of sunitinib and TSA increased cancer cell death via mitochondrial apoptosis.
- TSA did not affect sunitinib's direct target, receptor tyrosine kinase signaling.
- Sunitinib and TSA combination significantly inhibited the growth of sunitinib-resistant RCC cells.
Conclusions:
- TSA reduces sunitinib resistance in RCC by inducing intracellular metabolome shifts related to energy metabolism.
- This study identifies a novel mechanism for HDAC inhibitors in overcoming drug resistance in RCC.
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