Non-oncology drug (meticrane) shows anti-cancer ability in synergy with epigenetic inhibitors and appears to be involved passively in targeting cancer cells

by Selleckchem | Nov 17 2023

Emerging evidence suggests that chemotherapeutic agents and targeted anticancer drugs have serious side effects on the healthy cells/tissues of the patient. To overcome this, the use of non-oncology drugs as potential cancer therapies has been gaining momentum. Herein, we investigated one non-oncology drug named meticrane (a thiazide diuretic used to treat essential hypertension), which has been reported to indescribably improve the therapeutic efficacy of anti-CTLA4 in mice with AB1 HA tumors. In our hypothesis-driven study, we tested anti-cancer potential meticrane in hematological malignance (leukemia and multiple myeloma) and liver cancer cell lines. Our analysis showed that: 1) Meticrane induced alteration in the cell viability and proliferation in leukemia cells (Jurkat and K562 cells) and liver cancer (SK-hep-1), however, no evidence of apoptosis was detectable. 2) Meticrane showed additive/synergistic effects with epigenetic inhibitors (DNMT1/5AC, HDACs/CUDC-101 and HDAC6/ACY1215). 3) A genome-wide transcriptional analysis showed that meticrane treatment induces changes in the expression of genes associated with non-cancer associated pathways. Of importance, differentially expressed genes showed favorable correlation with the survival-related genes in the cancer genome. 4) We also performed molecular docking analysis and found considerable binding affinity scores of meticrane against PD-L1, TIM-3, CD73, and HDACs. Additionally, we tested its suitability for immunotherapy against cancers, but meticrane showed no response to the cytotoxicity of cytokine-induced killer (CIK) cells. To our knowledge, our study is the first attempt to identify and experimentally confirm the anti-cancer potential of meticrane, being also the first to test the suitability of any non-oncology drug in CIK cell therapy. Beyond that, we have expressed some concerns confronted during testing meticrane that also apply to other non-oncology drugs when considered for future clinical or preclinical purposes. Taken together, meticrane is involved in some anticancer pathways that are passively targeting cancer cells and may be considered as compatible with epigenetic inhibitors.

Comments:

Your study explores the potential anti-cancer properties of meticrane, a non-oncology drug originally used to treat hypertension. Here's a summary of the key findings and implications of your research:

1. **Effects on Cell Viability and Proliferation**: Meticrane treatment resulted in alterations in cell viability and proliferation in leukemia cells (Jurkat and K562 cells) and liver cancer cells (SK-hep-1), although apoptosis was not detected. This suggests that meticrane may impact cancer cell growth and survival through non-apoptotic mechanisms.

2. **Synergistic Effects with Epigenetic Inhibitors**: Meticrane exhibited additive or synergistic effects when combined with epigenetic inhibitors such as DNMT1/5AC, HDACs/CUDC-101, and HDAC6/ACY1215. This suggests that meticrane may enhance the anti-cancer effects of these inhibitors, potentially through complementary mechanisms.

3. **Transcriptional Changes**: Genome-wide transcriptional analysis revealed that meticrane treatment induced changes in gene expression associated with non-cancer pathways. Importantly, these differentially expressed genes were found to correlate favorably with survival-related genes in cancer genomes, suggesting a potential impact on cancer cell survival mechanisms.

4. **Molecular Docking Analysis**: Molecular docking analysis showed that meticrane exhibited considerable binding affinity scores against PD-L1, TIM-3, CD73, and HDACs. This suggests that meticrane may interact with these proteins, which are known to be involved in cancer-related pathways.

5. **Immunotherapy Considerations**: While meticrane showed promise in other aspects, it did not appear to enhance the cytotoxicity of cytokine-induced killer (CIK) cells in immunotherapy. This finding indicates that meticrane may not be effective in enhancing the immune response against cancer cells mediated by CIK cells.

6. **Future Clinical Considerations**: Your study highlights the potential of non-oncology drugs like meticrane in cancer therapy. It also raises important considerations and challenges for further clinical or preclinical investigations of such drugs. These concerns should be addressed to determine the safety and efficacy of repurposing non-oncology drugs for cancer treatment.

In summary, your research provides valuable insights into the potential anti-cancer properties of meticrane, especially in combination with epigenetic inhibitors, and its impact on gene expression patterns in cancer cells. However, further research is needed to better understand the mechanisms involved and to evaluate the safety and efficacy of meticrane in clinical settings, including its potential in combination therapies and immunotherapy.