Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells

Abstract

BackgroundCD133-positive cells in hepatocellular carcinoma (HCC) exhibit cancer stem cell (CSC)-like properties as well as resistance to chemotherapeutic agents and ionizing radiation; however, their function remains unknown. In this paper, we identified a hitherto unknown mechanism to overcome CD133-induced resistance to anticancer therapy.MethodsWe applied an alternative approach to enrich the CD133-positive HCC population by manipulating 3D culture conditions. Defense mechanisms against reactive oxygen species (ROS) in CSC spheroids were evaluated by fluorescence image-based phenotypic screening system. Further, we studied the effect of sulfasalazine on ROS defense system and synergistic therapeutic efficacy of anticancer therapies both in culture and in vivo HCC xenograft mouse model.ResultsHere, we found that oxidative stress increase CD133 expression in HCC and increased CD133 expression enhanced the capacity of the defense system against ROS, and thereby play a central role in resistance to liver cancer therapy. Moreover, ablation of CD133 attenuated not only the capacity for defense against ROS, but also chemoresistance, in HCC through decreasing glutathione (GSH) levels in vitro. Sulfasalazine, a potent xCT inhibitor that plays an important role in maintaining GSH levels, impaired the ROS defense system and increased the therapeutic efficacy of anticancer therapies in CD133-positive HCC but not CD133-negative HCC in vivo and in vitro.ConclusionThese results strongly indicate functional roles for CD133 in ROS defense and in evading anticancer therapies in HCC, and suggest that sulfasalazine, administered in combination with conventional chemotherapy, might be an effective strategy against CD133-positive HCC cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0511-7) contains supplementary material, which is available to authorized users.

Carboxypeptidase A4 promotes proliferation and stem cell characteristics of hepatocellular carcinoma

“…ALDH1 activation and high CD44 expression have also been reported as markers to identify cell populations enriched for CSCs in breast cancer, gastric cancer and lung cancer . In general, only a minority of cells (<5%) in the total tumour cell population are believed to be stem cells, but the flow cytometric analysis of several studies revealed that the percentage of cells expressing CD133, CD44 or ALDH1 differed between several HCC cell lines (from <1% to more than 90%) . In our study, the results shown in Figure indicate that more cells with high CPA4 expression expressed stem cell markers; more Bel7402 cells expressed stem cell markers than HepG2 cells.…”

“…28 In general, only a minority of cells (<5%) in the total tumour cell population are believed to be stem cells, but the flow cytometric analysis of several studies revealed that the percentage of cells expressing CD133, CD44 or ALDH1 differed between several HCC cell lines (from <1% to more than 90%). [29][30][31] In our study, the results shown in Figure 3 indicate that more cells with high CPA4 expression expressed stem cell markers; more Bel7402 cells expressed stem cell markers than HepG2 cells. Transfection with CPA4 plasmids increased stem cell marker expression, indicating that CPA4 may induce the proportion of stem cell marker-expressing cells.…”

Sulfasalazine could modulate the CD44v9‐xCT system and enhance cisplatin‐induced cytotoxic effects in metastatic bladder cancer

“…The initial finding of SSZ as a potent inhibitor of xCT was investigated in lymphoma cells and increasing numbers of studies reported the anticancer effects of SSZ in various cancers, such as glioma, prostate cancer, and pancreatic cancer . Furthermore, SSZ was shown to enhance the therapeutic efficacy of chemotherapies . In the present study, we examined the effectiveness of SSZ in BC cells using the MBT‐2V cell line, which has a highly metastatic potential with high CD44v9 expression.…”

“…16 Furthermore, SSZ was shown to enhance the therapeutic efficacy of chemotherapies. 21,29 In the present study, we examined the effectiveness of SSZ in BC cells using the MBT-2V cell line, which has a highly metastatic potential with high CD44v9 expression. CD44v9 was recently found to interact with xCT by combining together on the tumor cell surface.…”

Identificação de vias moduladas por microRNAs na diferenciação celular e manutenção da pluripotência em células humanas

“…Esta abordagem tem sido amplamente utilizada para as mais diversas finalidades, como, por exemplo, na identificação de novos tratamentos para o câncer, infecções por microorganismos ou de doenças cardiovasculares (EULALIO et al, 2012;LOVE et al, 2017;MANNING et al, 2017;PASCOALINO et al, 2016;SONG et al, 2017). Em outro exemplo, um grupo da Coréia do Sul realizou um screening com uma biblioteca de compostos químicos em CTEh, com o intuito de identificar compostos que poderiam induzir estados iniciais de diferenciação.…”