Lumiflavin increases the sensitivity of ovarian cancer stem‐like cells to cisplatin by interfering with riboflavin

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.

LncRNA WDFY3-AS2 promotes cisplatin resistance and the cancer stem cell in ovarian cancer by regulating hsa-miR-139-5p/SDC4 axis

“…Cancer stem cells (CSCs) are important drivers of therapeutic resistance in many tumor types [ 7 ], and represent a population of tumor cells that exhibit stem-like properties including the ability to differentiate and undergo self-renewal, thus allowing them to support sustained tumor growth and heterogeneity [ 8 , 9 ]. Owing to their properties, CSCs are thought to be important drivers of tumor metastasis and other malignant processes [ 10 , 11 ], and developing approaches to eliminating these cells is therefore vital to decrease the odds of OC therapeutic resistance or relapse [ 12 ].…”

Lumiflavin Reduces Cisplatin Resistance in Cancer Stem-Like Cells of OVCAR-3 Cell Line by Inducing Differentiation

“…As reported in previous studies, CSCs were isolated through magnetic bead sorting by using a magnetic cell sorting system (MACS) ( 11 , 18 ). Briefly, the cells were harvested from each of the OVCAR-3 cell lines and OVCAR-3/DDP.…”

“…To detect the purity and cell surface marker expression of CSCs (CD133+) of OVCAR-3/DDP or OVCAR-3, briefly ( 11 , 18 ), the CD44 (antibodies, BD Biosciences), CD24 (antibodies, BD Biosciences), CD117 antibodies (Boster Biological Technology, China), and CD133 antibodies (Miltenyi Biotec) were tested by flow cytometry (BD Biosciences, San Jose, CA) according to the manufacturer’s instructions. Cells from each group were collected and centrifuged at 1,500 g for 5 min and suspended with PBS twice.…”

“…Lumiflavin, a flavin analogue ( Figure 1 ), is a competitive inhibitor of riboflavin. Our previous studies have proved that lumiflavin reduced the enrichment of ovarian cancer CSCs to riboflavin, lessened the tolerance of CSCs to DDP, improved the damage effect of chemotherapy drugs, and enhanced the radiotherapy effect on CSCs ( 11 ). However, the effect of lumiflavin on the development of drug resistance in ovarian cancer, especially on drug-resistant CSCs, is still vague.…”

“…It can also induce the differentiation of breast cancer CSCs, reduce the invasion and migration of cells, and improve the sensitivity to tumor treatment ( 17 ). Previous studies showed that the effect of lumiflavin was related to its reduction in the CSC proportion ( 11 , 18 ). Therefore, we speculated that lumiflavin may affect the differentiation of ovarian cancer CSCs.…”