Inhibition of TRPM7 with carvacrol suppresses glioblastoma functions in vivo.

Glioblastoma (GBM) is the most prevalent and aggressive type of primary human brain tumours originating in the central nervous system. Despite the fact that current treatments involve surgery, chemotherapy (Temozolomide), and radiation therapy, the prognosis for patients diagnosed with GBM remains extremely poor. The standard treatment is not only unable to completely eradicate the tumour cells, but also tumour recurrence after surgical resection presents a major challenge. Furthermore, adjuvant therapies including radiation and chemotherapy have high cytotoxicity which causes extensive damage to surrounding healthy tissues and treatment is usually halted before GBM is fully eradicated. Finally, most GBM cases demonstrate temozolomide resistance, a common reason for GBM treatment failure. Therefore, there is an urgent need to develop a suitable alternative therapy that targets GBM specifically and has low cytotoxicity for healthy cells. We previously reported that transient receptor potential melastatin 7 (TRPM7) channels are aberrantly upregulated in GBM, and inhibition of TRPM7 reduced GBM cellular functions including proliferation, migration, and invasion. This suggests TRPM7 is a potential therapeutic target for GBM treatment. In this study, we investigated the effects of the TRPM7 inhibitor, carvacrol, on human GBM cell lines U87 and U251 in vivo. With the use of a flank xenograft GBM mouse model, we demonstrated that carvacrol significantly reduced the tumour size in both mice injected with U87 and U251 cells, decreased p-Akt protein level and increased p-GSK3ß protein levels. Therefore, these results suggest that carvacrol may have therapeutic potential for GBM treatment.

Role of TRPM2 in brain tumours and potential as a drug target.

Ion channels are ubiquitously expressed in almost all living cells, and are the third-largest category of drug targets, following enzymes and receptors. The transient receptor potential melastatin (TRPM) subfamily of ion channels are important to cell function and survival. Studies have shown upregulation of the TRPM family of ion channels in various brain tumours. Gliomas are the most prevalent form of primary malignant brain tumours with no effective treatment; thus, drug development is eagerly needed. TRPM2 is an essential ion channel for cell function and has important roles in oxidative stress and inflammation. In response to oxidative stress, ADP-ribose (ADPR) is produced, and in turn activates TRPM2 by binding to the NUDT9-H domain on the C-terminal. TRPM2 has been implicated in various cancers and is significantly upregulated in brain tumours. This article reviews the current understanding of TRPM2 in the context of brain tumours and overviews the effects of potential drug therapies targeting TRPM2 including hydrogen peroxide (H2O2), curcumin, docetaxel and selenium, paclitaxel and resveratrol, and botulinum toxin. It is long withstanding knowledge that gliomas are difficult to treat effectively, therefore investigating TRPM2 as a potential therapeutic target for brain tumours may be of considerable interest in the fields of ion channels and pharmacology.

Role of TRPM7 kinase in cancer.

Cancer is the second leading cause of death worldwide and accounted for an estimated 9.6 million deaths, or 1 in 6 deaths, in 2018. Despite recent advances in cancer prevention, diagnosis, and treatment strategies, the burden of this disease continues to grow with each year, with dire physical, emotional, and economic consequences for all levels of society. Classic characteristics of cancer include rapid, uncontrolled cell proliferation and spread of cancerous cells to other parts of the body, a process known as metastasis. Transient receptor potential melastatin 7 (TRPM7), a Ca2+- and Mg2+-permeable nonselective divalent cation channel defined by the atypical presence of an α-kinase within its C-terminal domain, has been implicated, due to its modulation of Ca2+ and Mg2+ influx, in a wide variety of physiological and pathological processes, including cancer. TRPM7 is overexpressed in several cancer types and has been shown to variably increase cellular proliferation, migration, and invasion of tumour cells. However, the relative contribution of TRPM7 kinase domain activity to cancer as opposed to ion flux through its channel pore remains an area of active discovery. In this review, we describe the specific role of the TRPM7 kinase domain in cancer processes as well as mechanisms of regulation and inhibition of the kinase domain.

Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions.

Glioblastoma (GBM) is the most common malignant primary brain tumour originating in the CNS. Median patient survival is <15 months with standard treatment which consists of surgery alongside radiation therapy and temozolomide chemotherapy. However, because of the aggressive nature of GBM, and the significant toxicity of these adjuvant therapies, long-term therapeutic effects are unsatisfactory. Thus, there is urgency to identify new drug targets for GBM. Recent evidence shows that the transient receptor potential melastatin 7 (TRPM7) cation channel is aberrantly upregulated in GBM and its inhibition leads to reduction of GBM cellular functions. This suggests that TRPM7 may be a potential drug target for GBM treatment. In this study, we assessed the effects of the specific TRPM7 antagonist waixenicin A on human GBM cell lines U87 or U251 both in vitro and in vivo. First, we demonstrated in vitro that application of waixenicin A reduced TRPM7 protein expression and inhibited the TRPM7-like currents in GBM cells. We also observed reduction of GBM cell viability, migration, and invasion. Using an intracranial xenograft GBM mouse model, we showed that with treatment of waixenicin A, there was increased cleaved caspase 3 activity, alongside reduction in Ki-67, cofilin, and Akt activity in vivo. Together, these data demonstrate higher GBM cell apoptosis, and lower proliferation, migration, invasion and survivability following treatment with waixenicin A.

In vitro effects of hydrogen peroxide on rat uterine contraction before and during pregnancy.

AIM: To assess the in vitro effect of hydrogen peroxide (H2O2) on uterine contractions in pregnant and non-pregnant rats. METHODS: The study was performed at the Department of Physiology, College of Medicine, King Saud University from December 2016 to October 2017. Intact uterine samples were obtained from non-pregnant (n=7-8) and term-pregnant (n=6-7) rats. Small longitudinal uterine strips were dissected and mounted in an organ bath. Isometric force measurements were used to assess the effect of 400, 800, and 1000 µM H2O2 on spontaneous uterine contractions and contractions induced by oxytocin (5 nM), high calcium (Ca+2) solution (6 mmol/L), and high potassium chloride (KCl) solution (60 mmol/L). RESULTS: In both term-pregnant and non-pregnant uterine strips, H2O2 elicited a biphasic response, consisting of a transient contraction followed by a persistent decrease in spontaneously generated contractions, contractions induced by oxytocin, and contractions induced by high Ca+2 (all P<0.01, compared with controls) in a concentration-dependent manner. The effect of H2O2 was more pronounced in non-pregnant than in pregnant rats (P<0.05). In both groups, H2O2 failed to relax uterine strips pre-contracted with high-KCl solution (P>0.05 compared with controls). CONCLUSION: H2O2 was shown to be a potent uterine relaxant in pregnant and non-pregnant states. The pregnant uterus better withstood the inhibitory effect of H2O2 than non-pregnant uterus.

Epidemiology of senile prostatic enlargement among elderly men in Arar, Kingdom of Saudi Arabia.

BACKGROUND AND AIM: Senile prostatic enlargement due to benign prostatic hyperplasia (BPH) is a common problem among older men, and is responsible for considerable disability. This study was conducted to determine the prevalence and determinants of the clinically diagnosed prostatic enlargement among elderly men in Arar, Northern Saudi Arabia. METHODS: This cross-sectional study was carried out on all consented elderly males attending the outpatient clinic of the urology department of Arar Central Hospital from February 2017 to July 30, 2017. Each participant underwent a general examination and digital per rectal to detect general chronic diseases, obesity and prostatic enlargement. Data were analyzed by SPSS version 16, using descriptive statistics and Chi-squared test. RESULTS: Among 81 elderly male participants in the study, 19.8% had clinically diagnosed senile prostatic enlargement (SPE) and 3.7% had prostatic tumors. There was significant relation between SPE and age as 6.2% of cases were 60-69 years, 43.8% were 70-79 years and 44.0% were 80 years or more (p<0.05). There was also significant relation between SPE and obesity as 62.5% of cases were obese and 37.5% were non obese (p<0.05). There was no significant relation with marital status, smoking or diabetes mellitus (p<0.05). CONCLUSION: Senile prostatic enlargement is one of the significant important issues in public health in Arar city, Northern Saudi Arabia. The prevalence of this condition reaches 19.3%, thereby placing even greater burden on the quality of life of the elderly and on the health system in the region.