Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy

Pietropaolo, Giuseppe; Pugliese, Daniela; Armuzzi, Alessandro; Guidi, Luisa; Gasbarrini, Antonio; Rapaccini, Gian Lodovico; Wolf, Federica I.; Trapani, Valentina

doi:10.3390/nu12113277

Cited by 13 publications

(12 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some anticancer drugs, including cisplatin (CDDP), a platinum based anticancer drug, and cetuximab and panitumumab, chimeric and fully human monoclonal antibodies to the epidermal growth factor receptor (EGFR), often cause a side effect of hypomagnesemia [ 5 ]. Cetuximab downregulates TRPM6-mediated Mg 2+ influx by interfering with EGF signaling [ 6 ]. In addition, anti-EGFR agents induce kidney and cardiac disorders [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of Chemoresistance by Mg2+ Deficiency through Elevation of ATP Binding Cassette Subfamily B Member 1 Expression in Human Lung Adenocarcinoma A549 Cells

Onuma

Manabe

Yoshino

et al. 2021

Cells

View full text Add to dashboard Cite

Several anticancer drugs including cisplatin (CDDP) induce hypomagnesemia. However, it remains fully uncertain whether Mg2+ deficiency affects chemosensitivity of cancer cells. Here, we investigated the effect of low Mg2+ concentration (LM) on proliferation and chemosensitivity using human lung adenocarcinoma A549 cells. Cell proliferation was reduced by continuous culture with LM accompanied with the elevation of G1 phase proportion. The amounts of reactive oxygen species (ROS) and stress makers such as phosphorylated-ataxia telangiectasia mutated and phosphorylated-p53 were increased by LM. Cell injury was dose-dependently increased by anticancer drugs such as CDDP and doxorubicin (DXR), which were suppressed by LM. Similar results were obtained by roscovitine, a cell cycle inhibitor. These results suggest that LM induces chemoresistance mediated by ROS production and G1 arrest. The mRNA and protein levels of ATP binding cassette subfamily B member 1 (ABCB1) were increased by LM and roscovitine. The LM-induced elevation of ABCB1 and nuclear p38 expression was suppressed by SB203580, a p38 MAPK inhibitor. PSC833, an ABCB1 inhibitor, and SB203580 rescued the sensitivity to anticancer drugs. In addition, cancer stemness properties were suppressed by SB203580. We suggest that Mg2+ deficiency reduces the chemotherapy sensitivity of A549 cells, although it suppresses cell proliferation.

show abstract

Section: Introductionmentioning

confidence: 99%

Upregulation of Chemoresistance by Mg2+ Deficiency through Elevation of ATP Binding Cassette Subfamily B Member 1 Expression in Human Lung Adenocarcinoma A549 Cells

Onuma

Manabe

Yoshino

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…Hypomagnesemia is frequently associated with EGFRI treatment because the blocking of the activation of EGFRs decreases the expression of transient receptor potential melastatin 6 (TRPM6) regulating the absorption and reabsorption of magnesium in the intestine and renal tubules 8,9 . In this study, we found that serum zinc and magnesium levels were significantly correlated.…”

Section: Discussionmentioning

confidence: 72%

“…EGFRI treatment, especially anti‐EGFR monoclonal antibodies, is known to decrease serum magnesium levels 8,9 . Serum magnesium levels were measured in 15 of the 16 patients treated with anti‐EGFR antibodies, and the mean ± SD of serum magnesium levels was 1.6 ± 0.27 mg/dL (normal range 1.8–2.5 mg/dL).…”

Section: Resultsmentioning

confidence: 99%

Possible involvement of zinc deficiency in epidermal growth factor receptor inhibitor‐induced xerotic dermatitis

Tohyama

Sakaguchi

Nishina

et al. 2021

The Journal of Dermatology

View full text Add to dashboard Cite

Cancer treatment with epidermal growth factor receptor inhibitors (EGFRIs) often induces severe xerotic dermatitis. Various irritants facilitate development of dermatitis in xerotic skin. As zinc deficiency plays a role in the development of irritant dermatitis, we measured serum zinc levels in 25 patients with xerotic dermatitis due to treatment with EGFRIs. Of these patients, nine were treated with EGFR tyrosine kinase inhibitors and 16 were treated with anti‐EGFR antibody alone or in combination with other anticancer agents. Serum zinc levels of all patients were lower than the normal range of >80 μg/dL, with a mean ± SD serum zinc level of 56.4 ± 11.7 μg/dL. These were correlated with serum magnesium levels in patients. As the serum magnesium level is known to be reduced by the inhibition of EGFR, a similar mechanism may also be involved in decreasing the serum zinc level. Among 21 patients treated with zinc supplementation for more than 2 months, xerotic dermatitis markedly improved, with an increase of serum zinc levels in 16 patients. The other five patients exhibited no significant improvement in their skin condition, and insufficient and unstable increase in serum zinc levels. In conclusion, zinc supplementation may be beneficial in supportive care for patients with EGFRI‐induced xerotic dermatitis.

show abstract

“…In line with the role of EGF signalling in TRPM6 activation, hypomagnesemia is a common side effect of treatment with the EGFR antibody cetuximab, occurring in 20-30 % of the patients (18,91,92) . Cetuximab prevents the EGF-induced activation of TRPM6 in kidney and colon cells, indicating the hypomagnesemia can be attributed to a decrease in both renal and intestinal (re)absorption (18,93) . Hypomagnesemia is not reported in patients treated with EGFR TKI (94) .…”

Section: Luminal Mg 2+ Uptake In the Intestine And Distal Convoluted Tubulementioning

confidence: 99%

Genetic and drug-induced hypomagnesemia: different cause, same mechanism

2021

View full text Add to dashboard Cite

Magnesium (Mg2+) plays an essential role in many biological processes. Mg2+ deficiency is therefore associated with a wide range of clinical effects including muscle cramps, fatigue, seizures and arrhythmias. To maintain sufficient Mg2+ levels, (re)absorption of Mg2+ in the intestine and kidney is tightly regulated. Genetic defects that disturb Mg2+ uptake pathways, as well as drugs interfering with Mg2+ (re)absorption cause hypomagnesemia. The aim of this review is to provide an overview of the molecular mechanisms underlying genetic and drug-induced Mg2+ deficiencies. This leads to the identification of four main mechanisms that are affected by hypomagnesemia-causing mutations or drugs: luminal transient receptor potential melastatin type 6/7-mediated Mg2+ uptake, paracellular Mg2+ reabsorption in the thick ascending limb of Henle's loop, structural integrity of the distal convoluted tubule and Na+-dependent Mg2+ extrusion driven by the Na+/K+-ATPase. Our analysis demonstrates that genetic and drug-induced causes of hypomagnesemia share common molecular mechanisms. Targeting these shared pathways can lead to novel treatment options for patients with hypomagnesemia.

show abstract

Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy

Cited by 13 publications

References 39 publications

Upregulation of Chemoresistance by Mg2+ Deficiency through Elevation of ATP Binding Cassette Subfamily B Member 1 Expression in Human Lung Adenocarcinoma A549 Cells

Upregulation of Chemoresistance by Mg2+ Deficiency through Elevation of ATP Binding Cassette Subfamily B Member 1 Expression in Human Lung Adenocarcinoma A549 Cells

Possible involvement of zinc deficiency in epidermal growth factor receptor inhibitor‐induced xerotic dermatitis

Genetic and drug-induced hypomagnesemia: different cause, same mechanism

Contact Info

Product

Resources

About