Cancer is one of the leading causes of death in both men and women worldwide. One of the main changes associated with cancer progression, metastasis, recurrence, and chemoresistance is the change in ...the tumor immune microenvironment, especially immunosuppression. Cancer immunosuppression appears in multiple forms, such as inhibition of immuno-stimulant cells with downregulation of immuno-stimulant mediators or through stimulation of immuno-suppressive cells with upregulation of immunosuppressive mediators. One of the most immunosuppressive mediators that approved potency in lung cancer progression is indoleamine 2,3-dioxygenase (IDO) and its metabolite kynurenine (Kyn). The current review tries to elucidate the role of IDO/Kyn on cancer proliferation, apoptosis, angiogenesis, oxidative stress, and cancer stemness. Besides, our review investigates the new therapeutic modalities that target IDO/Kyn pathway and thus as drug candidates for targeting lung cancer and drugs that potentiate IDO/Kyn pathway and thus can be cancer-promoting agents.
•TLS increased uric acid, phosphate, and potassium.•TLS inhibited AMPK activity.•Decreased AMPK activity induced different chemoresistance mechanisms.
Cancer is a disease caused when cells divide ...uncontrollably and spread into surrounding tissues. There are different therapeutic modalities that control cancer growth, of which surgery, chemotherapy, and radiotherapy. Chemotherapy is a cancer treatment approach in which medications are used to inhibit cell proliferation and tumor multiplication, thus avoiding invasion and metastasis and thus eradicate cancer. One of the common complications associated with cancer chemotherapy is rapid lysis of expanding tumor cells, known as tumor lysis syndrome (TLS). TLS is associated with number of metabolic changes such as hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. Among the consequences of hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia is the inhibition of 5′ AMP-activated protein kinase (AMPK). Inhibition of AMPK induced different cancer chemo-resistance mechanisms such as cancer stem cells (CSCs), p-glycoproteins, Octamer-binding transcription factor 4 (OCT-4), homeobox protein NANOG, Krüppel-like factor 4 (KLF4) and immune microenvironment and thus leads to poor response to chemotherapy and even relapses after treatment. Our review aims to uncover new mechanisms underlying the metabolic consequences of tumor lysis on AMPK in tumor microenvironment. In this review, we also investigated the effect of AMPK on different cancer chemo-resistance mechanisms such as cancer stem cells, p-glycoproteins, OCT-4, NANOG, KLF4 and immune microenvironment.
Hepatocellular carcinoma (HCC) is the third foremost cause of cancer-related deaths. HCC has a very bad prognosis because it is asymptomatic in the early stages, resulting in a late diagnosis, and it ...is highly resistant to conventional chemotherapy. Such chemotherapies have been proven disappointing because they provide extremely low survival benefits. This study discloses that the STAT3/HIF-1α is an auspicious therapeutic attack site for conceivable repression of HCC development. A site that can be targeted by simultaneous administration of a STAT3 inhibitor in the context of HSP90 inhibition. 17-DMAG binds to HSP90 and constrains its function, resulting in the degradation of HSP90 client proteins HIF-1α and STAT3. Hypoxia recruits STAT3/HIF-1α complex within the VEGF promoter. Additionally, it was acknowledged that STAT3 is an essential mediator of VEGF transcription by direct binding to its promoter. Furthermore, it induces HIF-1α stability and enhances its transcriptional activity. Herein, we revealed that the combination therapy using 17-DMAG and nifuroxazide, a STAT3 inhibitor, repressed the diethylnitrosamine-induced alterations in the structure of the liver. This effect was mediated via decreasing the levels of the HSP90 client proteins HIF-1α and pSTAT3 resulting in the suppression of the STAT3/HIF-1α complex transcriptional activity. To conclude, 17-DMAG/NFXZD combination therapy-induced disruption in the STAT3/HIF-1α loop led to a potential antiangiogenic activity and showed apoptotic potential by inhibiting autophagy and inducing ROS/apoptosis signaling. Additionally, this combination therapy exhibited promising survival prolongation in mice with HCC. Consequently, the use of 17-DMAG/NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.
•17-DMAG and nifuroxazide suppressed STAT3/HIF-1α complex transcriptional activity.•17-DMAG and nifuroxazide led to potential antiangiogenic and apoptotic activity.•17-DMAG and nifuroxazide prolonged the survival of mice with HCC.•STAT3/HIF-1α is a therapeutic attack site for repression of HCC development.•17-DMAG and nifuroxazide rendered an inspirational perspective for managing HCC.
Hyperinsulinemia, hyperglycemia, and chronic inflammation may play a role in hepatocellular carcinoma (HCC). Treatment of HCC patients with the antidiabetic medication metformin corrected the ...pathological changes of HCC by affecting proliferation, apoptosis, and angiogenesis. On the other hand, our review aims to uncover new pathways underlying metformin's anti-tumor action in the liver, focusing on immunological mediators and immune archetypes. In this review, we discuss the effect of metformin on restructuring the HCC immune microenvironment, such as dendritic cells, T cells, Tregs, macrophages, neutrophils, and myeloid-derived suppressors cells (MDSCs). Furthermore, Metformin also changes the expression pattern of immune mediators in HCC immune microenvironment, including programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), transforming growth factor-beta (TGF-β), Interleukin 12 (IL-12), indoleamine 2,3 dioxygenase (IDO), forkhead box protein P3 (FOXP3), and interferon-gamma (IFN-γ). This review summarizes a state-of-the-art understanding of the molecular mechanisms underlining novel anticarcinogenic approaches of metformin through modulation of liver cancer immune microenvironment both on the cellular and molecular scales, which aids in regaining immune fitness and thus better prognosis. The changes in tumor immune architecture and mediators induced by metformin make it a robust antineoplastic agent with multiple mechanisms of action, especially for people with diabetes and HCC.
Liver fibrosis is a liver disease in which there is an excessive buildup of extracellular matrix proteins, including collagen. By regulating cytokine production and the inflammatory response, heat ...shock proteins (HSPs) contribute significantly to a wider spectrum of fibrotic illnesses, such as lung, liver, and idiopathic pulmonary fibrosis by aiding in the folding and assembly of freshly synthesized proteins, HSPs serve as chaperones. HSP70 is one of the key HSPs in avoiding protein aggregation which induces its action by sending unfolded and/or misfolded proteins to the ubiquitin-proteasome degradation pathway and antagonizing influence on epithelial-mesenchymal transition. HSP47, on the other hand, is crucial for boosting collagen synthesis, and deposition, and fostering the emergence of fibrotic disorders. The current review aims to provide light on how HSP70 and HSP47 affect hepatic fibrogenesis. Additionally, our review looks into new therapeutic approaches that target HSP70 and HSP47 and could potentially be used as drug candidates to treat liver fibrosis, especially in cases of comorbidities.
Overexposure to carcinogenic precursor, benzoapyrene BaP, modulates the lung immune microenvironment. The present review seeks to elucidate novel pathways behind the tumor effect of BaP in the lungs, ...emphasizing immunomodulatory mediators and immune cells. In this review, BaP reprograms lung immune microenvironment through modulating transforming growth factor-beta (TGF-β), programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), Interleukin 12 (IL-12), indoleamine 2,3 dioxygenase (IDO), forkhead box protein P3 (FOXP3) and interferon-gamma (IFN-γ) levels. Moreover, BaP modulated lung immune cellular architecture such as dendritic cells, T cells, Tregs, macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs). All mentioned changes in immune architecture and mediators lead to the induction of lung cancer.
•HCC immune microenvironment affected CD47+ cancer stem cells.•CTLA4, IDO-1, PDL-1 increased percentage of CD47+ cancer stem cells.•IL-17, IL-10, Galectin-1, and TGF-B increased CD47+ cancer stem ...cell population.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. There are different therapeutic approaches to cancer eradication such as chemotherapy, radiotherapy, and surgery. The fuel for treatment resistance is heterogeneity, which also has significant effects on cancer therapies and biomarker research. One of the most common causes of cancer chemoresistance and relapse is the presence and percentage of cancer stem cells (CSCs), among them CD47+ CSCs. Besides, the change in the tumor microenvironment (TME) stands as one of the main factors for the failure of chemotherapeutic protocols. The current review aims to focus on how the change in immune mediators such as TGF-β, IL-10, IL-17, IDO, Gal-1, PD-L1, and CTLA-4 affect CD47+ CSCs in HCC and thus open a new era towards developing new approaches for prevention of HCC relapse and stemness through different immune modulation approaches. Then we investigate some drugs that have a dual effect on both TME and CD47 CSCs and thus the best choice in comorbidities.
Hepatocellular carcinoma (HCC) is on the rise worldwide, and its incidence in diabetic patients is two to three times that of non-diabetics. Current therapeutic options fail to provide considerable ...survival benefits to patients with HCC. There is a strong possibility that the FDA-approved antidiabetic combination of empagliflozin and metformin could show complementary effects to control HCC progression. However, their multitarget effects have not yet been studied on HCC development. Therefore, the present study aims to evaluate the antitumorigenic activity of this combination in non-diabetic mice with diethylnitrosamine-induced HCC. Empagliflozin/metformin combination prolonged survival and improved histological features of mice livers. Additionally, Empagliflozin/metformin showed anti-inflammatory potential and relieved oxidative stress. On the one hand these effects are likely attributed to the ability of metformin to inactivate NF-κB in an AMPK-dependent mechanism and on the other hand to the ability of the empagliflozin to inhibit the MAPKs, p38 and ERK1/2. Empagliflozin also showed a less robust effect on AMPK than that of metformin. Moreover, empagliflozin enhanced the autophagy inducing activity of metformin. Furthermore, empagliflozin/metformin exhibited increased apoptotic potential. Consequently, empagliflozin augmented the antitumorigenic function of metformin by exerting better control of angiogenesis, and metastasis. To conclude, our findings suggest empagliflozin as an ideal adjunct to metformin for the inhibition of HCC progression. In addition, since the incidence of hypoglycemia is minimal due to insulin-independent mechanism of action of both treatments, empagliflozin/metformin could be a promising therapeutic modality for the management of diabetic patients with HCC; and even non diabetic ones.
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•Empagliflozin/metformin combination prolonged the survival of mice with HCC.•Empagliflozin/metformin showed apoptotic and anti-inflammatory potential.•Metformin inhibited NF-κB signals in an AMPK-dependent mechanism in murine HCC.•Empagliflozin inhibited the MAPKs, p38 and ERK1/2 in mice livers with HCC.•Empagliflozin is as an ideal adjunct to metformin for the inhibition of HCC progression.
Metformin and empagliflozin combined therapy may have complementary effects that go beyond the well-recognized targets of their monotherapy through AMPK activation. Therefore, the current study was ...designed to investigate for the first time the hepatoprotective effects of such combination therapy in the carbon tetrachloride (CCl4)-induced hepatic fibrosis model in mice.
Determination of liver enzymes and the liver content of oxidative stress parameters, and hydroxyproline were performed biochemically. ELISA was performed to measure PDGF-BB, TNF-α, TGF-β, TIMP-1, AMPK, p-mTOR, NF-κB P65 binding activity, p38 MAPKα, JNK1/2 and ERK1/2. Real-time qPCR was conducted to determine Col1a1 and α-SMA. In addition, histopathological examination using H&E and Masson's trichrome stain were performed for determination of histopathological changes.
Empagliflozin inhibited the activation of p38 MAPK and ERK1/2 and exhibited a weak AMPKα stimulation. On the other hand, metformin exerted a more robust stimulatory action on the AMPKα that was accompanied by a notable decrease in the NF-κB nuclear binding activity and a decline in the p-mTOR levels. Nevertheless, the effect of metformin on MAPK kinases was insignificant. Our results revealed that blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhanced the antifibrotic effect of metformin and augmented its AMPK-induced NF-κB inactivation.
As diabetes is one of the most common risk factors for liver fibrosis, the use of antidiabetic drugs is expected to improve therapeutic outcome. Therefore, metformin/empagliflozin combined therapy could be promising in preventing hepatic inflammation and fibrosis via exhibiting complementary effects particularly in diabetic patients.
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•Metformin/empagliflozin demonstrated hepatoprotective activity in vitro and in vivo.•Metformin/empagliflozin prolonged survival of mice with liver fibrosis.•Empagliflozin inhibited the activation of p38 MAPK and ERK1/2.•Metformin activated AMPKα and inhibited NF-κB nuclear binding activity.•Metformin/empagliflozin exhibited prominent anti-inflammatory effects.
Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models
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enhancing AMPK activity. Yet, the ...protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated
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enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis.
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