KiSS-1 Modulation by Epigenetic Agents Improves the Cisplatin Sensitivity of Lung Cancer Cells.
Beretta. Giovanni Luca GL; Alampi. Desirè D; Corno. Cristina C; Carenini. Nives N; Corna. Elisabetta E; Perego. Paola P
Key Findings
- Pre‑treating lung cancer cells with SAHA (a histone deacetylase inhibitor) or AZA (a DNA methyltransferase inhibitor) increases the release of the metastasis‑suppressor protein KiSS‑1.
- Giving SAHA or AZA before cisplatin creates a stronger synergistic killing effect than giving them at the same time.
- Adding the peptide kisspeptin‑10 (KP10) further enhances cisplatin‑induced cell death in both cisplatin‑sensitive and -resistant lung cancer cells.
- In mice, the SAHA‑plus‑cisplatin schedule that worked best in cells also reduced tumor growth.
Practical Outcomes
- For most biohackers, this study offers limited direct use because it involves prescription chemotherapy and epigenetic drugs that require medical supervision. It does highlight that kisspeptin‑10 can boost chemotherapy effectiveness, which may inform future clinical protocols, but it is not a safe or actionable supplement regimen for self‑experimenters.
Summary
Scientists found that two drugs that change how genes are packaged (SAHA and AZA) can make lung cancer cells more sensitive to the chemotherapy drug cisplatin, and that adding the peptide kisspeptin‑10 (KP10) boosts this effect even more. The best results came when the gene‑changing drugs were given before cisplatin, and the combination also shrank tumors in mice.
Abstract
Epigenetic alterations my play a role in the aggressive behavior of Non-Small Cell Lung Cancer (NSCLC). Treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) has been reported to interfere with the proliferative and invasive potential of NSCLC cells. In addition, the DNA methyltransferase inhibitor azacytidine (AZA, vidaza) can modulate the levels of the metastasis suppressor KiSS-1. Thus, since cisplatin is still clinically available for NSCLC therapy, the aim of this study was to evaluate drug combinations between cisplatin and SAHA as well as AZA using cisplatin-sensitive H460 and -resistant H460/Pt NSCLC cells in relation to KiSS-1 modulation. An analysis of drug interaction according to the Combination-Index values indicated a more marked synergistic effect when the exposure to SAHA or AZA preceded cisplatin treatment with respect to a simultaneous schedule. A modulation of proteins involved in apoptosis (p53, Bax) was found in both sensitive and resistant cells, and compared to the treatment with epigenetic agents alone, the combination of cisplatin and SAHA or AZA increased apoptosis induction. The epigenetic treatments, both as single agents and in combination, increased the release of KiSS-1. Finally, the exposure of cisplatin-sensitive and -resistant cells to the kisspeptin KP10 enhanced cisplatin induced cell death. The efficacy of the combination of SAHA and cisplatin was tested in vivo after subcutaneous inoculum of parental and resistant cells in immunodeficient mice. A significant tumor volume inhibition was found when mice bearing advanced tumors were treated with the combination of SAHA and cisplatin according to the best schedule identified in cellular studies. These results, together with the available literature, support that epigenetic drugs are amenable for the combination treatment of NSCLC, including patients bearing cisplatin-resistant tumors.
Study Information
pubmed
2024
2024-05-06T00:00:00.000Z
10.3390/ijms25095048
2
43