Abstract
Here, we used lumiflavin, an inhibitor of riboflavin, as a new potential therapeutic chemosensitizer to ovarian cancer stem‐like cells (CSCs). This study demonstrates that the enrichment of riboflavin in CSCs is an important cause of its resistance to chemotherapy. Lumiflavin can effectively reduce the riboflavin enrichment in CSCs and sensitize the effect of cisplatin Diamminedichloroplatinum (DDP) on CSCs. In this study, CSCs of human ovarian cancer cell lines HO8910 were separated using a magnetic bead (CD133+). We also show the overexpression of the mRNA and protein of riboflavin transporter 2 and the high content of riboflavin in CSCs compared to non‐CSCs (NON‐CSCs). Moreover, CSCs were less sensitive to DDP than NON‐CSCs, whereas, the synergistic effect of lumiflavin and DDP on CSCs was more sensitive than NON‐CSCs. Further research showed that lumiflavin had synergistic effects with DDP on CSCs in increasing mitochondrial function damage and apoptosis rates and decreasing clonic function. In addition, we found that the combination of DDP and lumiflavin therapy in vivo has a synergistic cytotoxic effect on an ovarian cancer nude mice model by enhancing the DNA‐damage response and increasing the apoptotic protein expression. Notably, the effect of lumiflavin is associated with reduced riboflavin concentration, and riboflavin could reverse the effect of DDP in vitro and in vivo. Accordingly, we conclude that lumiflavin interfered with the riboflavin metabolic pathways, resulting in a significant increase in tumour sensitivity to DDP therapy. Our study suggests that lumiflavin may be a novel treatment alternative for ovarian cancer and its recurrence.
Highlights
Ovarian cancer is among the most common malignant tumours in women
Human ovarian cancer cell lines HO8910 were purchased from Shanghai Cell Bank of Chinese Academy of Sciences; ribofla‐ vin was purchased from National Institutes for Food and Drug Control of China; lumiflavin was purchased from Toronto Research Chemicals (TRC) of Canada; Accuri C6 flow cytometry was made by BD Biosciences of USA; Real‐time Quantitative PCR Detecting System System and Western blot system were made by Bio‐Rad
3.1 | Differences observed between the NON‐Cancer stem‐like cells (CSCs) and CSCs of HO8910 cell line in terms of riboflavin levels, sensitivity to DDP, mRNA and protein expression of riboflavin transporter 2 (RFT2), as well as the synergetic effect DDP combined with different dosages of lumiflavin
Summary
Ovarian cancer is among the most common malignant tumours in women. Lumiflavin, a natural inhibitor of riboflavin (Figure 1), can prevent the conversion of riboflavin into flavin adenine dinucleotide (FAD) and flavin mononucleotide, and can interfere with the physiological effect of riboflavin.[11,12] In this study, we explore the efficacy of lu‐ miflavin, a riboflavin inhibitor, in both murine models and human cell lines in vivo and in vitro and found that it synergized with DDP ther‐ apy in ovarian cancer. Our results show that the key pathways, such as riboflavin metabolic pathway, are essential in the action mainte‐ nance of CSCs and DDP chemoresistance, suggesting an important clinical application of lumiflavin in ovarian cancer therapy
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