Effect of dapagliflozin and/or L‐arginine on solid tumor model in mice: The interaction between nitric oxide, transforming growth factor‐beta 1, autophagy, and apoptosis

Kabel, Ahmed M.; Arab, Hany H.; Elmaaboud, Maaly A. Abd

doi:10.1111/fcp.12661

Cited by 7 publications

(4 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some studies revealed L-arginine enhances arginine deiminase induced human lymphoma cell growth inhibition through NF-kBp65 and p53 expression ( Shu et al, 2014 ). In a solid Ehrlich carcinoma (SEC) mouse model, L-arginine increased survival rates, elevated total nitrate/nitrite levels in tissues, upregulated p53, JNK, beclin-1, and caspase-3 expression, and improved histopathological features ( Kabel et al, 2021 ). The cytostatic effect of relaxin on MCF-7 breast cancer cells may rely on its ability to stimulate endogenous production of NO through activation of the L-arginine-NO pathway ( Bani et al, 1995 ).In addition, L-Arginine induces NO production and potentiates the anticancer effect of 5-FU in Breast Adenocarcinoma ( Bala and Panditharadyula, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

L-arginine combination with 5-fluorouracil inhibit hepatocellular carcinoma cells through suppressing iNOS/NO/AKT-mediated glycolysis

Hu,

Xing,

Fan

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

L-arginine can produce nitric oxide (NO) under the action of inducible nitric oxide synthase (iNOS), while 5-fluorouracil (5-FU) can induce the increase of iNOS expression. The present study was to investigate the mechanism of L-arginine combined with 5-FU regulating glucose metabolism of hepatocellular carcinoma (HCC) through iNOS/NO/AKT pathway. The combination of L-arginine and 5-FU resulted in decreased cell survival and exhibited synergistic cytotoxic effects in HepG2 and SMMC7721 cells. Meanwhile, L-arginine increased 5-FU inhibitory effect on HepG2 and SMMC7721 cells by increasing NO production. Co-treatment with L-arginine and 5-FU resulted in a significant decrease in both G6PDH and LDH enzymatic activities, as well as reduced levels of ATP and LD compared to treatment with L-arginine or 5-FU alone. Moreover, the combination of L-arginine and 5-FU resulted in a decrease in the expression of GLUT1, PKM2, LDHA, p-PI3K and p-AKT. Furthermore, the combination demonstrated a synergistic effect in downregulating the expression of HIF-1α and β-catenin, which were further diminished upon the addition of shikonin, a specific inhibitor of PKM2. LY294002 treatment further reduced the expression of GLUT1, PKM2, and LDHA proteins induced by combined L-arginine and 5-FU treatment compared to the combined group. However, the reduction in p-PI3K, p-AKT, and GLUT1 expression caused by L-arginine and 5-FU combination was also reversed in HepG2 and SMMC7721 cells with iNOS knockdown, respectively. Additionally, the combination of L-arginine and 5-FU led to a greater reduction in the enzymatic activity of ALT, AST, G6PDH and LDH, as well as a significant reduction in hepatic index, AFP, AFP-L3, ATP and LD levels in a rat model of HCC. Moreover, the simultaneous administration of L-arginine and 5-FU significantly improved the gross morphology of the liver, reduced nuclear atypia, inhibited the proliferation of cancer cells, and decreased the expression levels of p-PI3K, p-AKT, GLUT1, PKM2, and LDHA, while iNOS expression was increased in the combination group. Taking together, L-arginine and 5-FU combination resulted in the inhibition of enzymes in aerobic glycolysis via the iNOS/NO/AKT pathway, which led to the suppression of glucose metabolism and downregulation of nuclear transcription factors, thereby impeding the proliferation of hepatocellular carcinoma cells.

show abstract

Section: Discussionmentioning

confidence: 99%

L-arginine combination with 5-fluorouracil inhibit hepatocellular carcinoma cells through suppressing iNOS/NO/AKT-mediated glycolysis

Hu,

Xing,

Fan

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Nevertheless, Kaji et al reported the anti-cancer effect of SGLT2 inhibition to be exerted independently of the systemic glycemic status, although cellular glucose-uptake was not assessed here. 174 Other mechanistic pathways on the anti-cancer effects of SGLT2 blockade were suggested by other studies, showing that SGLT2 inhibition (i) decreases pro-carcinogenic inflammation, 175 (ii) activates AMPK, which leads to inactivation of the protooncogene sonic hedgehog, 176 (iii) suppresses cancer progression by inhibiting the Hippo signalling pathway through downregulating YAP1 expression. 177 In contrast, however, Korfhage and colleagues reported an increased intestinal adenoma burden in female, but not in male APC min mice, when treated with canagliflozin, 178 a result that needs further mechanistic elucidation.…”

Section: Effects Of Sodium-glucose Cotransporter 2 Inhibitors On Cancermentioning

confidence: 93%

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence

Sayour,

Paál,

Ameri

et al. 2024

European Heart Journal

View full text Add to dashboard Cite

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

show abstract

“…Dapagliflozin is one of sodium-glucose cotransporter-2 (SGLT2) inhibitors that are marking a new era in the treatment of T2D due to showing significant mortality improvement in patients with CVD [8,9].…”

Section: Introductionmentioning

confidence: 99%

The vascular impact of dapagliflozin, liraglutide, and atorvastatin alone or in combinations in type 2 diabetic rat model

Medany

Hammadi

Khalifa

et al. 2022

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

Diabetic dyslipidemia is a significant contributor in the pathogenesis of type 2 diabetes (T2D). The study aimed at comparing the effect of dapagliflozin, liraglutide, and atorvastatin alone or their combinations on lipids and inflammatory markers and their vascular impact in T2D rats. There were 56 male albino rats included in the study and divided into two main groups. Group A (8 rats) served as normal control. Group B (48 rats) were streptozotocin-nicotinamide-induced diabetic rats. Subgroups (B-1, B-2, B-3, B-4, B-5, and B-6) received (no medications, dapagliflozin, liraglutide, atorvastatin, dapagliflozin + atorvastatin, and liraglutide + atorvastatin), respectively. Urine albumin/creatinine ratio (UACR), glycosylated hemoglobin (HBA1c), fasting serum glucose (FSG), serum low-density lipoproteincholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), TGs, lipoprotein(a) Lp (a), serum thyrotropin (TSH), highly sensitive C-reactive protein (hs-CRP) and advanced glycation end products (AGEs), were assessed. Qualitative and quantitative histological examination of kidneys focused on renal corpuscles. Dapagliflozin improved the studied parameters but with statistically insignificant increase in LDL-C, Lp (a) and significant increase in UACR. Atorvastatin improved the studied parameters but with statistically insignificant increase in FSG and HbA1C. Liraglutide and the combination groups significantly improved all studied parameters. Histologically, liraglutide and atorvastatin produced therapeutic effect, while dapagliflozin depicted nephrotoxic effect. Combination groups resulted in better effects with normalization of most of renal corpuscles. There were positive correlations between LDL-C and hs-CRP, AGEs, TSH and mesangial expansion. Combination of atorvastatin with liraglutide can improve its vasculoprotective effect. Moreover, combination of atorvastatin with dapagliflozin can ameliorate its possible nephrotoxic effect.

show abstract

Effect of dapagliflozin and/or L‐arginine on solid tumor model in mice: The interaction between nitric oxide, transforming growth factor‐beta 1, autophagy, and apoptosis

Cited by 7 publications

References 45 publications

L-arginine combination with 5-fluorouracil inhibit hepatocellular carcinoma cells through suppressing iNOS/NO/AKT-mediated glycolysis

L-arginine combination with 5-fluorouracil inhibit hepatocellular carcinoma cells through suppressing iNOS/NO/AKT-mediated glycolysis

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence

The vascular impact of dapagliflozin, liraglutide, and atorvastatin alone or in combinations in type 2 diabetic rat model

Contact Info

Product

Resources

About