Abstract
Magnesium, the second most predominant intracellular cation, plays a crucial role in many physiological functions; magnesium-based biomaterials have been widely used in clinical application. In a variety of cancer types, the high intracellular concentration of magnesium contributes to cancer initiation and progression. Therefore, we initiated this study to investigate the likelihood of confounding magnesium with cancer therapy. In this study, the anti-tumor activity of magnesium and underlying mechanisms were assessed in bladder cancer both in vitro and in vivo. The results indicated that the proliferation of bladder cancer cells was inhibited by treatment with a high concentration of MgCl2 or MgSO4. The apoptosis, G0/G1 cell cycle arrest, autophagy, and ER stress were promoted following treatment with MgCl2. However, the migratory ability of MgCl2 treated cells was similar to that of control cells, as revealed by the trans-well assay. Besides, no significant difference was observed in the proportion of CD44 or CD133 positive cells between the control and MgCl2 treated cells. Thus, to improve the therapeutic effect of magnesium, VPA was used to treat cancer cells in combination with MgCl2. As expected, combination treatment with MgCl2 and VPA could markedly reduce proliferation, migration, and in vivo tumorigenicity of UC3 cells. Moreover, the Wnt signaling was down-regulated, and ERK signaling was activated in the cells treated with combination treatment. In conclusion, the accurate utilization of MgCl2 in targeting autophagy might be beneficial in cancer therapy. Although further studies are warranted, the combination treatment of MgCl2 with VPA is an effective strategy to improve the outcome of chemotherapy.
Highlights
Bladder cancer ranks the second most frequent urological malignancy worldwide, with an estimated 549,393 newly diagnosed and approximately 199,922 deaths each year [1]
Many in vitro and in vivo studies suggest that Valproic acid (VPA) exhibits the characteristic of high effectiveness and relatively low toxicity profile. Considering these benefits of VPA, the present study examined the synergistic effect of the combination of VPA and magnesium in cancer therapy
To determine the effects of magnesium on the bladder cancer cell viability in vitro, we analyzed the impact of different concentrations of magnesium on the bladder cancer cell lines
Summary
Bladder cancer ranks the second most frequent urological malignancy worldwide, with an estimated 549,393 newly diagnosed and approximately 199,922 deaths each year [1]. Cisplatin-based chemotherapy, a standard first-line treatment of choice based on studies demonstrating improved survival outcomes, has been the mainstay for bladder cancer for decades [5, 6]. Patients who receive traditional chemotherapeutic regimens might suffer from the significant risk of off-target toxicity and the development of resistance to drugs. To overcome these limitations, in recent years, many alternative strategies, including nanotechnology, have been developed to improve the therapeutic outcome of chemotherapy [7]. Nanocomposite particles have received significant attention as useful drug carriers for cancer therapy. In this study, we made an attempt to determine the anti-tumor effect of magnesium in bladder cancer
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