The Future  Prospective: Potential Magnesium and Calcium for Detracting Side Effect Cisplatin

 

Syafika Alaydrus1,2*, Ajeng Diantini1, Riezki Amalia1, Sriwidodo3, Anis Yohana Chaerunisa3, Nasrul Wathoni3

1Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy,

Universitas Padjadjaran, West Java 45363, Indonesia.

2Department of Pharmacy, STIFA Pelita Mas Palu, Central Sulawesi, Indonesia.

3Department of Pharmaceutics and Pharmaceutical Technology,

Faculty of Pharmacy, Universitas Padjadjaran, West Java 45363, Indonesia.

*Corresponding Author E-mail: syafikaalaydrus39@gmail.com

 

ABSTRACT:

Cancer has been caused by more death globally and is associated with magnesium and calcium intake with some cancers. Some studies are shown as a protective agent against chemotherapy-induced nephrotoxicity and neurotoxicity. Despite magnesium and calcium are the opposite in inflammation, reabsorption regulation, and other physiological processes. However, it is important to maintain the balance between magnesium and calcium related to the micronutrients' physiological functions. One of the cancer drugs can lead to hypomagnesemia and hypocalcemia electrolytes such as cisplatin. The purpose of this article is to review the cisplatin mechanism in electrolyte disorder and the association between potential magnesium and calcium for therapy of some cancer.

 

KEYWORDS: Magnesium, Calcium, Cancer, Cisplatin.

 

 


INTRODUCTION:

Bray et al. 1 and Miller et al. 2 state a rapid increase in cancer and mortality. Between 2014 and 2019, cancer mortality will continue to fall in both sexes3. The epidemiological studies have shown the risk factor of cancer incidence in humans: the deficiency of   magnesium4. Demir et al., 5 found in leukemia patients, there is a decrease in Magnesium levels. Furthermore, high prostate cancer is related to blood magnesium level6.

 

Magnesium plays an essential role in the structure and several metabolic reactions of the human body. Three hundred metabolic reactions influence amino acid, protein, nucleid acid, protein, and ion transport.  The role of calcium is important because calcium has a role in apoptosis, proliferation, and differentiation7.

 

Magnesium ion and calcium ion have a role in managing the diverse and important cellular processes, such as treatment, the transformation of neoplastic, gene transcription, and the immune system. The biologically contradictory characteristic of calcium ion and magnesium ion make them important to compete in cellular interaction8. The research conducted by Cohort states that  1.170 breast cancer patients shown the relation between the calcium and magnesium intake with breast cancer survival, and the ratio between Ca: Mg is more than 2.598.

 

The increased morbidity and mortality from cancer because of the failure of chemotherapy9,10. Magnesium has an important role that is to reduce the effect of chemotherapeutic agents, such as cisplatin11. Cisplatin and derivatives are the major targets in DNA. The studies showed cisplatin-induced hypomagnesemia in rats12. The study shows magnesium can affect the MCF-7 cells, but it is not as strong as cisplatin as a conventional chemotherapeutic agent. Despite the side effects of chemotherapy drugs, Magnesium is potentially selected as the supplement for breast cancer13.

Finding new methods and materials for treating cancer is needed due to the effective and safe method in carrying the drugs and bioactive molecules to specific cell14. In modern pharmaceutics research, this research is intriguing15. The role of this review is to determine the potential of magnesium and calcium to reduce the side effects of chemotherapy agents, especially cisplatin16.

 

MAGNESIUM  AND CALCIUM:

Magnesium: Magnesium is an important electrolyte mineral role for its structure and function in the human body. Magnesium helps the metabolism of various nutrients such as protein synthesis, synthesis, and breakdown of fatty acids and contributes to DNA and RNA repairs, immune system, maintains heart rhythm or rhythm, regulates blood glucose levels, nerve function and muscle contraction, and almost all hormonal reactions and maintaining cellular ionic balance 17. Magnesium is needed for the function of Na/K-ATPase pumps. Hypermagnesemia usually occurs in patients with end-stage kidney disease or known as Addison's disease.

 

Usually, the body can be deficient in magnesium (hypomagnesemia) because of heart failure, excessive sweating, chronic diarrhea, indigestion, alcoholism, or taking drugs such as diuretics18, antibiotics, and chemotherapy agents such as cisplatin19.

 

The studies show that tumor progression can be considered caused by mineral homeostasis disturbances such as magnesium20. In patients' cancer, increasing expression magnesium transport channel can induce ascending the intracellular mineral concentration, resulting in mineral growth21.

 

Magnesium deficiency caused an increase in intracellular sodium and lots of potassium in exit and into extracellular. Those are cells can hypokalemia their only treatment magnesium. Magnesium influences calcium homeostasis in two mechanisms. The first is that most calcium channels depend on magnesium. When intracellular magnesium concentrations are high, calcium is transported into cells, and the sarcoplasmic reticulum is inhibited. In magnesium deficiency, the opposite occurs, and as a result, intracellular calcium concentrations increase. Second, magnesium is needed for the release and action of the parathyroid hormone. Magnesium is associated with average calcium in which patients with hypomagnesemia have low plasma calcium, which can be returned to normal by giving calcium supplementation after magnesium deficiency is corrected22.

 

During energy metabolism, magnesium plays a role in bone mineralization, muscle contraction, and nerve impulse transmission. Magnesium forms the complexity between ATP, ADP, and GTP, required for enzymes involved in the transfer of phosphate groups such as glucokinase, phosphofructokinase, phosphoglycerate-kinase, pyruvate-kinase, DNA polymerase, ribonuclease, adenyl cyclase, phosphodiesterases, guanylate-cyclase, ATPases, and GTPases23.

 

Calcium: Calcium is an important mineral for controlling the contraction of skeletal muscles, plays a role in the delivery of nerve impulses and muscle activation, builds strong bones and teeth, and helps the process of blood clotting. Hypercalcemia can be caused by hyperparathyroidism, kidney disease, thyroid disorders, lung diseases such as tuberculosis, excessive vitamin D, calcium, antacid supplements, and theophylline drugs. In contrast, calcium deficiency is caused by kidney failure, hypoparathyroidism, vitamin D deficiency, pancreatitis, prostate cancer, indigestion, and certain drugs, including heparin, osteoporosis drugs, and antiepileptic drugs24,25.

 

Molecular Elements of Magnesium Transport in Tumours: The latest magnesium finding states that it plays a role as transporters in common feature26. Most of the studies in mice and other species evidence that TRPM7 is necessary for magnesium homoeostasis27,28 and embryonic development29,30.

 

1. Transient Receptor Potential Melastatin 6 Cation Channel (TRPM6) and Transient Receptor Potential Melastatin 7 Cation Channel (TRPM7)

The channel kinases TRPM6 and TRPM7 potentially function to maintain cellular metabolism of Mg2+ homeostasis31,32 and other essential metals such as Ca2+ and Zn2+ 33. TRPM6 regulates TRPM7 activity by phosphorylation as TRPM6 kinase was established to cross-phosphorylate TRPM7 but not vice versa, a bifunctional protein that combines calcium and magnesium permeable cation channel properties with protein kinase activity34,35.

 

Transient receptor potential melastatin 6 (TRPM6)  is shown to function in active epithelial Mg2+ transport in the intestine and kidney tubules36. TRPM6 is vital for magnesium homeostasis, and mutations in TRPM6 or TRPM7 have been linked to Mg2+ deficiency in human disease37. Human magnesium homeostasis is tightly regulated and depends on the balance between intestinal absorption and renal excretion38.

 

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is the protein that contains a protein kinase fused to an ion channels magnesium, calcium, and zink, and an α-kinase that phosphorylates downstream substrates39. TRPM7, as the main regulator for all parts of the magnesium mammals homoeostasis40. The molecular mechanisms controlling magnesium balance in the organism are not well understood41. The research reported the TRPM7 identification is very important for cellular control and homeostasis of the whole body of  magnesium42 and embryonic development 40.

 

The proliferation of some tumor cell types requires TRPM7, including leukaemia43,44, retinoblastoma45, and carcinoma cells of pancreatic46, breast47, gastric48, head, and neck49. Melastatin-like transient receptor potential 6 and 7 (TRPM6, TRPM7), which are and cations (Magnesium, calcium) conducting channels, during cell proliferation of human osteoblasts50.

 

 

The effects of TRPM7 in pathologic cell differentiation has been intensively investigated in cancer cells, including the pancreas, ovary, breast, and adenocarcinoma of lungs and prostate51,52. Expression of TRPM7 in these cancers was associated with increased expression of proliferative markers53. The studies, particularly in cell controls, refer that VEGFR and EGFR influence TRPM7 activity and Ca2+ and Mg2+ homeostasis. The kinase domain can also influence TRPM7 channel function54. Modifying in TRPM7 activity and Mg2+ homeostasis have a significant effect on tyrosine kinase signaling55. Therefore, knowing mechanisms whereby these drugs cause hypomagnesemia is important so that undesired side effects can be executed in a mechanism-specific act39,56. Inactivation of TRPM7 kinase in mice results in dilated spleens, reduced T-cell proliferation, and detracted calcium entry57.


 

Figure 1: The Association Molecular Pathways of TRPM7 in Regulating Tumour Growth and Invasion.“TRPM7-dependent Magnesium influences signaling in PI3K/Akt/mTOR protein translation regulatory pathway. TRPM7-dependent magnesium uptake activated by growth factors (GFs), hypoxia, and other signals can open the TRPM7 channel and increase cell proliferation. The PI3K signaling cascade is a Ly29002 inhibitor that appears as an integration point between magnesium availability and cell proliferation behavior in the metabolic phase, macromolecular synthesis. On the other hand, it has been suggested that the unfold of TRPM7 channels affects its kinase function by causing a local increase in calcium and magnesium concentration, which regulates the recruitment/targeting of TRPM7 kinase substrates. The kinase domain may transmit intracellular signals via the phosphorylation of downstream targets, such as annexin I, myosin IIA, IIB and IIC, and calpain, which all of a role for TRPM7 in the membrane and cytoskeletal for cell migration and invasion. Become different TRPM7 expression and activity has been associated with increased proliferation or migration in several various cancer cell types”.


2. Receptor Tyrosine Kinase Signaling

Magnesium is a crucial divalent cation required for the activity of protein kinases, including RTKs (VEGFR, EGFR, FGFR, PDGFR) and non-receptor tyrosine kinases (Src, Abl, Jak, FAK, SOCS) 58. In cell-based studies, high Mg2+ concentration causes increased tyrosine kinase activity59. Tyrosine kinase signaling is associated with cause unregulated cell growth in cancer60.

 

Data crystallography experiments showed that two Mg2+ molecules are required for enzyme activity and phosphoryl transfer: one bound to ATP (Mg-ATP) situated between the small and large lobes of the kinase domain, bound to β and γ-phosphates and to the aspartate of the DFG (Asp-Phe-Gly), which are the first residues to be activated in protein kinases; and in high [Mg2+] conditions, another Mg2+ binds to α and γ-phosphates and the asparagine amide nitrogen within the catalytic loop61.

 


Figure 2: Importance of Mg2+ for the kinase catalytic activity. Two Mg2+ molecules are required for enzymatic activity and phosphoryl transfer: one bound to ATP (Mg-ATP) resigned between the small (N-lobe) and large lobe (C-Lobe) of the kinase domain, and another Mg2+ resigned in the catalytic loop. (1) Mg-ATP is the first to bind to the enzyme followed by Mg2+; (2) the kinase binds to the protein substrate and catalyzes the transfer of the phosphoryl group; (3) phosphorylated protein and Mg2+ are released; and (4) Mg-ADP is independent, and the catalytic cycle is ended.

 


RELATIONSHIP BETWEEN MAGNESIUM AND CALCIUM IN CANCER: Magnesium and calcium are important elements that regulate various cellular processes, like proliferation, migration, and apoptosis. The antagonist role of magnesium and calcium often shows an inverse functional relationship. Magnesium and calcium are important in vitamin D metabolism62.

 

There is a complex relationship between cancer and magnesium. Magnesium plays an important role in cell functions such as energy metabolism, protein and DNA synthesis, and activation of the cytoskeleton63. A prospective cross-sectional study comparing serum magnesium levels of healthy people and breast cancer patients indicates a significant reduction of serum magnesium levels among people with breast cancer and healthy people64. The study Wesselink et al.65 showed that a higher magnesium intake was related to lower violence of chronic Chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe side-effect in colorectal cancer (CRC) patients, whereas no relation for calcium was found.


 

Table 1: The Results of Association of Magnesium and Calcium Intake in Some Cancer Development

Cancer Type

Experimental model

Subject

Result

Reference

Breast Cancer

Case-control study

She recruited 1050 case-patients and 1229 control subjects.

Effect on inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6).

66

Cohort study

1,170 participant women

a high Ca: Mg intake ratio (>2.59)

8

Colorectal

Cancer

Cohort study

 

Included 1169 newly diagnosed stage I-III Colorectal cancer

Higher concentrations of 25 (OH)D3 can lose mortality risk colorectal cancer in association with magnesium and calcium 

62

A case-control study and meta-analysis

Case Control of adenomas: (768 cases; 709 polyp-free control subjects

Meta-analysis of colorectal adenomas: (3 case-control studies and carcinomas (6 prospective cohort studies)

Case control : OR for every 100-mg/d increase: 0.81; 95% CI: 0.62, 1.06

Meta-analysis : OR: 0.87; 95% CI: 0.75, 1.00 about 13% and RR: 0.88; 95% CI: 0.81, 0.97 about 12%

67

Pancreatic Cancer

A cohort study

151 participants of 66 806 men and women aged 50–76 years

The longitudinal association between magnesium intake

68

Leukemia Cancer

Study group

42 patients in 40 control group

Zn, Mg and Mn (p=0.239) and Cu, Pb and Cd serum levels significantly lower with acute leukemia whereas

no significant  Co and Fe (p=0.323 and p=0.508)

5

Prostate Cancer

Biomarker sub-study of the Nashville Men's Health Study (NMHS)

494 NMHS participants

Ratio Ca: Mg OR = 2.81 (1.24, 6.36) associated with the increase of the risk of  high-grade prostate cancer

6

Case-control study

682 controls

0.73 (95% CI = 0.51–1.03) and 0.64 (95% CI = 0.43–0.96)

69

Lung Cancer

Cohort study

5435 participants, a prospective population-based and aged 55 years and older

A higher zinc intake about 42% (HR 0.58, 95 % CI 0.35; 0.94, P-for trend = 0.039) and iron (HR 0.58, 95 % CI 0.37; 0.92, P-for trend = 0.021) was related with the lower  risk of Lung cancer whereas calcium, copper, magnesium and selenium no association

70

 

 


CISPLATIN MECHANISM IN INDUCED MAGNESIUM: Nephrotoxicity consequence to the use of cisplatin has a fairly high mortality rate71,72. Cisplatin causes apoptotic cell death, which is characterized by apoptotic bodies in the renal cortex73. Apoptosis is caused by the intrinsic pathway of metabolic failure and the extrinsic pathway by death receptors activation. The accumulation of Platinum-induced nephrotoxicity74  in the proximal and distal epithelial cells with subsequent inflammation can change the cell membrane transporters and apoptosis75.

 

The confusing salt wasting is due to the chemotherapy mechanism. Since the magnesium reabsorption process is still not fully understood. Hypomagnesemia is a frequent complication of cisplatin chemotherapy and is experienced by up to 90% of patients if not corrected early 76. The clinical significance of hypomagnesemia is also uncertain. The clinical symptoms can be difficult to distinguish from symptoms related to the underlying disease or chemotherapy effects.

 

Furthermore, the renal tubular toxicity causes the tumor in some tissues like the neck, head, breast, and lung.  In the histopathologic study in rats, the low dose of magnesium can increase kidney toxicity and distribute the renal function77. In another study, premedication with intravenous magnesium demonstrated cisplatin-induced nephrotoxicity and an association between nephroprotective effect and serum magnesium levels78.

 

Magnesium deficiency and hypomagnesemia can cause gastrointestinal and renal losses. Cisplatin is largely unbound. It is different from oxaliplatin and carbolipatin79, and it is freely filtered through the glomerulus and subsequently accumulates in kidney tubular cells through organic cation80, and it may mediate nephrotoxicity, cisplatin can cause hypomagnesemia if the direct injury becomes higher than reabsorption in the ascending limb of the loop of Henle81 and causes hypokalemia paralysis82. Hypomagnesaemia is observed during therapies with cisplatin or the anti-EGFR antibody, cetuximab83; Cisplatin has recently been shown to cause hypomagnesemia by inhibiting the activation of EGF-dependent TRPM6, the main cation channel responsible for the transcellular absorption of Mg in the intestinal tubules kidneys84. Lacked research also examines that hypomagnesemia could carefully influence tumor response to cetuximab63.

 

CONCLUSION:

Cisplatin is a major antineoplastic agent with its wide and effective usage to treat solid tumors. It is known that the major electrolyte causes common toxicity in chemotherapy with cisplatin. However, it has some side effects on the bone marrow, cochlear, kidney, and gastrointestinal. The most common and important side effect is  Nephrotoxicity.  Some research has illustrated that numerous mechanisms, including DNA damage, inflammatory responses, and DNA damage, are closely related to cisplatin-induced nephrotoxicity. Therefore this kidney damage can be decreased by diuretics and the patient’s rehydration. The prevalence of nephrotoxicity caused by cisplatin is still high. Consequently, the therapy is important to be performed because it can attenuate cisplatin induced nephrotoxicity.

 

Although Cisplatin is more cytotoxic than Magnesium on MCF-7, magnesium can be considered a supplement agent in cancer treatment, including colorectal breast cancer, regarding chemotherapy drugs' side effects on pancreatic cancer. The magnesium loss from vomiting and chronic diarrhea of cisplatin toxicity and site effects can substitute for magnesium supplements. Thus administration of magnesium is beneficial to patients to avoid hypomagnesemia. Future research should explain how Mg is related to preventing cancer by regulating vital affairs in signal transduction pathways and the cell cycle.

 

TRPM 6 and TRPM 7 regulate cellular magnesium homeostasis, where magnesium can influence cell behavior. There is a missing link between magnesium availability and primary cell function in cancer; TRPM 7 expression signal relationship is via PI3K / Akt / mTOR. Therefore, TRPM7 is important in cancer stem cell regulation, and TRPM7 could be a therapeutic target for oncogenesis in cellular magnesium homeostasis.

 

ACKNOWLEDGEMENT:

The authors wish to acknowledge the contributions of the process of writing this review article.

 

CONFLICT OF INTEREST:

All authors (SA, AD, RA, S, AYC, NW) declare that they have no conflict of interest.

 

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Received on 07.11.2020            Modified on 27.03.2021

Accepted on 14.05.2021           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(1):481-488.

DOI: 10.52711/0974-360X.2022.00078