Magnesium-Assisted Cisplatin Inhibits Bladder Cancer Cell Survival by Modulating Wnt/β-Catenin Signaling Pathway

Abstract

Magnesium, an essential mineral micronutrient, plays a role in the activation of various transporters and enzymes. The present study aimed to investigate the possibility of applying magnesium to enhance the efficacy of cisplatin which is still ranked as one of the major chemotherapeutic drugs for bladder cancer patients. Results showed that the survival rate and colony formation of bladder cancer cells were reduced by combinatorial treatment with cisplatin and magnesium chloride (MgCl2). The proportion of apoptotic cells was also increased in UC3 bladder cancer cells treated with a combination of cisplatin and MgCl2. Most importantly, a marked decrease in nuclear β-catenin was observed in cells that received cisplatin treatment. In addition, the nuclear β-catenin in cisplatin treated cells was further down-regulated by supplementing MgCl2. 6-bromoindirubin-3′-oxime (BIO), an inhibitor of glycogen synthase kinase-3 (GSK-3) that activates the Wnt/β-catenin signaling pathway by modulating β-catenin activity, was thus applied to further exploit the role of this signaling pathway in magnesium aided cancer treatment. The survival rate of bladder cancer cells was decreased by BIO treatment at concentrations of 1.0, 2.5 and 5.0 μM accompanied by increased β-catenin expression. However, the expression of β-catenin in MgCl2-treated cells was lower than in untreated cells under the same BIO concentration. The expression of cleaved caspase-3, cleaved caspase-9 and microtubule-associated protein 1 light chain 3- II (LC3-II) was highest in cells treated with MgCl2 and 5.0 μM BIO among the examined groups. Our findings reveal that magnesium could contribute to cisplatin-based chemotherapy by moderately regulating the Wnt/β-catenin signaling pathway.

Remodeling tumor microenvironment with natural products to overcome drug resistance

“…The development of drug resistance in cancer cells cannot be separated from the regulation of the tumor microenvironment, in which the interaction of immune cells, tumor stroma and tumor cells gradually establishes resistance of cancer cells. In the study of overcoming drug resistance in cancer cells, we found that the combination of cisplatin and magnesium chloride (MgCl 2 ) could regulate the Wnt/β-catenin signaling pathway to enhance the cisplatin effect and use exosomes to control ferroptosis was also effectively inhibited cancer ( 240 , 241 ). Targeted drugs are often considered to be efficient therapies for cancer, but unfortunately, targeted therapies are all subject to varying degrees of resistance.…”

Metal ions and nanometallic materials in antitumor immunity: Function, application, and perspective

“…In addition, intratumor injection of MgCl 2 was recently proven to enhance cellular immunity by regulating CD8 + T-cell activation and cytotoxicity [ 73 ]. In addition, magnesium supplementation has the potential to combat cisplatin resistance [ 82 ] and to modulate inflammatory factors, such as tumor necrosis factor (TNF-α) [ 83 ].…”

Melatonin regulates cancer migration and stemness and enhances the anti‐tumour effect of cisplatin

“…Combination therapies could reduce the likelihood of acquired resistance, shorten the duration of treatment and speed up recovery 12,13 . Cisplatin, a platinum‐containing anticancer drug, is a non‐specific modulator of the cell cycle and exhibits a strong anticancer effect by interacting with N 7 ‐guanine and N 3 ‐adenine on cancer cells, damaging the structures on the cell membrane, and inhibiting replication of cancer cells, ultimately leading to cancer cell necroptosis 14–17 . However, cisplatin also causes severe toxicities, including nephrotoxicity, peripheral neuropathy and ototoxicity.…”

“…12,13 Cisplatin, a platinumcontaining anticancer drug, is a non-specific modulator of the cell cycle and exhibits a strong anticancer effect by interacting with N 7 guanine and N 3 -adenine on cancer cells, damaging the structures on the cell membrane, and inhibiting replication of cancer cells, ultimately leading to cancer cell necroptosis. [14][15][16][17] However, cisplatin also causes severe toxicities, including nephrotoxicity, peripheral neuropathy and ototoxicity. Long-term exposure to cisplatin could cause cancer cells to develop drug resistance.…”