Tumor lysis syndrome promotes cancer chemoresistance and relapse through AMPK inhibition.

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.

Reprograming immune microenvironment modulates CD47 cancer stem cells in hepatocellular carcinoma.

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-ß, 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.

Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management.

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.

IDO/kynurenine pathway in cancer: possible therapeutic approaches.

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.

Metformin modulate immune fitness in hepatocellular carcinoma: Molecular and cellular approach.

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-ß), 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.

The dynamic interplay between AMPK/NFκB signaling and NLRP3 is a new therapeutic target in inflammation: Emerging role of dapagliflozin in overcoming lipopolysaccharide-mediated lung injury.

Acute lung injury (ALI) is one the most common causes of morbidity and mortality in critically ill patients. In this study, we examined for first time the role of dapagliflozin (DPGZ) in lipopolysaccharide (LPS)-induced ALI in rats and determined the underlying molecular mechanisms by evaluating the effects of DPGZ on adenosine monophosphate kinase (AMPK), nuclear transcription factor kappa B, nucleotide-binding and oligomerization domain-like receptor 3 inflammasome activation. Treatment of acute lung injured rats with either low dose (5 mg/kg) or high dose (10 mg/kg) DPGZ significantly decreased oxidative stress by decreasing malondialdehyde and nitric oxide tissue levels with a significant increase in spectrophotometric measurements of superoxide dismutase, catalase, and reduced glutathione levels. DPGZ treatment resulted in a significant anti-inflammatory effect as indicated by suppression in myeloperoxidase activity, MCP-1, IL-1ß, IL-18, and TNF-α levels. DPGZ treatment also increased p-AMPK/t-AMPK with a significant reduction in NF-kB P65 binding activity and NFĸB p65 (pSer536) levels. These effects of DPGZ were accompanied by a significant reduction in NLRP3 levels and NLRP3 gene expression and a significant decrease in caspase-1 activity, which were also confirmed by histopathological examinations. We conclude that DPGZ antioxidant and anti-inflammatory activity may occur through regulation of AMPK/NFĸB pathway and inhibition of NLRP3 activation. These results suggest that DPGZ represents a promising intervention for the treatment of ALI, particularly in patients with type 2 diabetes.

Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application.

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.

Benzo[a]pyrene immunogenetics and immune archetype reprogramming of lung.

Overexposure to carcinogenic precursor, benzo[a]pyrene [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-ß), 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.

Blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhances the antifibrotic effect of metformin and augments its AMPK-induced NF-κB inactivation in mice intoxicated with carbon tetrachloride.

AIM: 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. MATERIALS AND METHODS: 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-ß, 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.

Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis.

Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via 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-1ß, 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 via 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.

A Novel Combination Therapy Using Rosuvastatin and Lactobacillus Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition.

Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and Lactobacillus and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/Lactobacillus significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1ß-driven pyroptotic activity was significantly reduced. Rosuvastatin/Lactobacillus showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1ß, and pro-IL-18. Furthermore, rosuvastatin/Lactobacillus reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.

AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma.

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKß, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-ß. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.

Immunosuppressive role of Benzo[a]pyrene in induction of lung cancer in mice.

AIM: Benzo[a]pyrene [BP] is one of the major carcinogenic precursors of cigarette smoke that primary affects the lung at its first proximity. The goal of the current research was to elucidate new mechanisms underlying the tumorigenic impact of oral BP in the lung of mice, with focus on immunosuppressive effects and cancer stemming properties. METHODS: Female albino mice (n = 44) were divided into 2 groups: normal control and BP group. BP was administered orally to mice (50 mg/kg body weight), twice a week for four weeks in succession. At the end of experiment (22 weeks), gene expression were measured for transforming growth factor-ß (TGF-ß), cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death ligand 1(PD-L1), forkhead box protein P3 (FOXP3) and interleukin 12 (IL-12) and CD83+, CD8+ and CD166+ cell percentage were measured in lung tissue. RESULTS: The results indicated the tumorigenic role of BP in the lung which was evidenced by histopathological examination. BP group also showed immunosuppressive role which evidenced by increased expression of lung TGF-ß, CTLA-4, PD-L1, FOXP3 genes and decreased expression of lung IL-12 gene compared with normal control group. BP group also showed decreased CD83+ cells, CD8+ cells and increased number of CD166+ cells. CONCLUSION: Our findings indicated that BP has immunosuppressive role in lung cancer besides increasing the percentage of cancer stem like cells.

Sorafenib effect on liver neoplastic changes in rats: more than a kinase inhibitor.

Although sorafenib was approved as antiangiogenic agent in case of hepatocellular carcinoma (HCC), the pathways mediating its antitumorigenic effects were not fully examined in vivo. This study was conducted to elucidate the molecular mechanisms underlying the antineoplastic effect of sorafenib in livers of rats exposed to the hepatocarcinogen diethyl nitrosamine (DENA) regarding oxidative stress, proliferation, and apoptotic pathways. Male albino rats were divided into three groups: normal control, DENA group, and sorafenib group. Sorafenib (10 mg/kg) was given daily to rats orally for 2 weeks, started 6 weeks after DENA (200 mg/kg, single i.p. dose). The histopathological results proved that sorafenib corrected neoplastic changes in the liver as evidenced by a decrease in size of hepatocellular foci. The liver index, glutathione, as well as Bcl-2 were significantly decreased in sorafenib group compared with DENA group. Sorafenib also exhibited antiproliferative effect through suppression of gene expression of cyclin D1 and ß-catenin. Thus, the apoptotic and proliferative pathways in HCC could be interrupted by sorafenib, supporting the role of sorafenib as antineoplastic agent and nominating it as a candidate drug for other neoplasms.

Effect of Pomegranate Hull Extract on Liver Neoplastic Changes in Rats: More than an Antioxidant.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. The current work was designed to elucidate the molecular mechanisms underlying the antitumorigenic effect of pomegranate hull extract (PHE) in livers of rats exposed to the hepatocarcinogen diethyl nitrosamine (DENA) with emphasis on oxidative stress, proliferation, and apoptosis. Male albino rats were divided into three groups: normal control, DENA group, and PHE group. PHE was given to rats orally 3 times weekly for 10 wk, 4 wk before and 6 wk after DENA (200 mg/kg, single i.p. dose). The results indicated a prophylactic effect of PHE against neoplastic changes in the liver, which was evidenced by the decrease of tumor size, liver index, and the anti-apoptotic protein Bcl-2; and the increase of glutathione. PHE group also showed decreased expression of liver cyclin D1 and ß-catenin genes compared with DENA group. It is proved that PHE has antitumorigenic effect and could be a candidate for anticancer drugs.