Mitochondrial activity is the key to the protective effect of β-Lapachone, a NAD+ booster, in healthy cells against cisplatin cytotoxicity

Background: Cisplatin (CDDP) is a first-line chemotherapeutic drug for treating various cancers. However, CDDP also damages normal cells and causes many side effects. Recently, CDDP has been demonstrated to kill cancer cells by targeting mitochondria. Protecting mitochondria might be a potential therapeutic strategy for CDDP-induced side effects. β-Lapachone (β-lap), a recognized NAD+ booster, has been reported to regulate mitochondrial activity. However, it remains unclear whether maintaining mitochondrial activity is the key factor in the protective effects of β-lap in CDDP-treated normal cells. Purpose: In this study, the protective effects of β-lap on mitochondria against CDDP cytotoxicity in normal cells were evaluated. Study design: In vitro cell models were used in this study, including 3T3 fibroblasts, human dermal fibroblasts, MCF-7 breast cancer cells, and MDA-MB-231 breast cancer cells. Methods: Cells were treated with CDDP and β-lap, and cell survival, NAD+, mitochondrial activity, autophagy, and ATP production were measured. Various inhibitors and siRNAs were used to confirm the key signal underlying the protective effects of β-lap. Results: The results demonstrated that β-lap significantly decreased CDDP cytotoxicity in normal fibroblasts. With various inhibitors and siRNAs, β-lap reduced CDDP-induced damage to normal fibroblasts by maintaining mitochondrial activity and increasing autophagy through the NQO1/NAD+/SIRT1 axis. Most importantly, the protective effects of β-lap in fibroblasts did not affect the therapeutic effects of CDDP in cancer cells. This study indicated that mitochondrial activity, energy production, and NQO1 levels might be crucial responses separating normal cells from cancer cells under exposure to CDDP and β-lap. Conclusion: β-lap could be a good synergistic drug for reducing the side effects of CDDP without affecting the anticancer drug effect.