RESUMO
Several studies have revealed that the combination of indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), and vitamin D reduces the risk of common types of cancers. Nonetheless, research on the deal concentrations used to test the impact of vitamin D on colon cancer is deficient. Along these lines, the aim of the present study was to evaluate the possible role of indomethacin and vitamin D as a preventative as well as a therapeutic operator for colon cancer growth induced by dimethylhydrazine (DMH) in male Albino rats. Fifty male albino rats were utilized in this examination; five groups were assigned from the animals (10 animals each): i) control group considered healthy animals; ii) carcinogen group that received DMH only; iii) prophylactic group; iv) vitamin D and indomethacin-treated group; and v) 5-flurouracil (5-FU) group. Western blot technique was used to determine the expression of carcinoembryonic antigen (CEA) and platelet-derived growth factor (PDGF). Overexpression of CEA and PDGF was noted in the carcinogenic group, while expression of CEA and PDGF in the prophylactic, vitamin D and indomethacin and 5-FU groups were markedly reduced. There was a likewise decline in tissue caspase-3 activity and antioxidant parameters in the carcinogenic group, while, there was an increase in these markers in the 5-FU group as well as the prophylactic and vitamin D and indomethacin groups. The combination of vitamin D and indomethacin markedly reduced the incidence and severity of colon cancer. The molecular, biochemical and histopathological analysis related with the oral administration of vitamin D and indomethacin display its capacity to limit the frequency of colorectal cancer.
RESUMO
One of the most lethal malignancies worldwide is colorectal cancer (CRC). Alterations in various signalling pathways, including PI3K-mTOR and NF-κB, have been reported in CRC with subsequent dysregulation of proliferation, apoptosis, angiogenesis and, questionably, autophagy processes. BEZ-235 (dactolisib) is a dual PI3K-mTOR inhibitor with potent anti-tumour activity. However, the observed toxicity of BEZ-235 necessitated the termination of its clinical trials. Hence, we aimed to evaluate the potential long-lasting anti-carcinogenic effects of adding diosmin (DIO, a natural NF-κB inhibitor) to BEZ-235 in HCT-116 CRC cells. The median inhibitory concentrations (IC50s) of BEZ-235 and/or DIO were evaluated in the HCT-116 CRC cell line. Caspase-3 activity was assessed colorimetrically, and p-Akt, NF-κB, CD1, VEGF and LC3B levels were assessed by ELISA. Additionally, LC3-II and P62 gene expression were assessed using qRT-PCR. The observed CIs (combination indices) and DRIs (dose reduction indices) confirmed the synergistic effect of DIO and BEZ-235. Co-administration of both drugs either in combination-1 (1 µM for BEZ-235, 250 µM for DIO) or in combination-2 (0.51 µM for BEZ-235 + 101.99 µM for DIO) inhibited the PI3K/Akt/mTOR/NF-κB axis, leading to the induction of apoptosis (via active caspase-3), and the inhibition of proliferation marker (CD1), angiogenesis marker (VEGF), autophagy protein (LC3B) and altered effects on LC3-IIandP62 gene expression. Our results reveal the synergistic chemotherapeutic effects of DIO combined with BEZ-235 in the HCT-116 CRC cell line and encourage future preclinical and clinical studies of this combination with reduced BEZ-235 concentrations to avoid its reported toxicity.
Assuntos
Diosmina/farmacologia , Imidazóis/farmacologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Células HCT116 , Humanos , FosforilaçãoRESUMO
Breast cancer is the current leading cause of cancer death in females worldwide. Although current chemotherapeutic drugs effectively reduce the progression of breast cancer, most of these drugs have many unwanted side effects. Salvianolic acid B (Sal-B) is a bioactive compound isolated from the root of Danshen Radix with potent antioxidant and anti-inflammatory properties. Since free radicals play a key role in the initiation and progression of tumor cells growth and enhance their metastatic potential, the current study was designed to investigate the antitumor activity of Sal-B and compare it with the antitumor activity of the traditional anticancer drug, cisplatin. In vitro, Sal-B decreased the human breast cancer adenocarcinoma (MCF-7) cells proliferation in a concentration and time dependent manner. In vivo and similar to cisplatin treatment, Sal-B significantly reduced tumor volume and increased the median survival when compared to tumor positive control mice group injected with Ehrlich solid carcinoma cell line (ESC). Sal-B decreased plasma level of malondialdehyde as a marker of oxidative stress and increased plasma level of reduced glutathione (GSH) as a marker of antioxidant defense when compared to control ESC injected mice. Either Sal-B or cisplatin treatment decreased tumor tissue levels of tumor necrosis factor (TNF-α), matrix metalloproteinase-8 (MMP-8), and Cyclin D1 in ESC treated mice. Contrary to cisplatin treatment, Sal-B did not decrease tumor tissue Ki-67 protein in ESC injected mice. Immunohistochemical analysis revealed that Sal-B or cisplatin treatment increased the expression of the apoptotic markers caspase-3 and P53. Although Sal-B or cisplatin significantly reduced the expression of the angiogenic factor vascular endothelial growth factor (VEGF) in ESC injected mice, only Sal-B reduced expression level of COX-2 in ESC injected mice. Our data suggest that Sal-B exhibits antitumor features against breast cancer cells possibly via enhancing apoptosis and reducing oxidative stress, inflammation, and angiogenesis.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama , Ácidos Cafeicos/farmacologia , Carcinoma de Ehrlich , Lactatos/farmacologia , Neovascularização Patológica , Estresse Oxidativo/efeitos dos fármacos , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma de Ehrlich/irrigação sanguínea , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Células MCF-7 , Camundongos , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recent studies suggest a potential role of bioactive lipids in acute kidney injury induced by lipopolysaccharide (LPS). The current study was designed to determine the profiling activities of various polyunsaturated fatty acid (PUFA) metabolizing enzymes, including lipoxygenases (LO), cyclooxygenase, and cytochrome P450 in the plasma of LPS-injected mice using LC-MS. Heat map analysis revealed that out of 126 bioactive lipids screened, only the 12/15-LO metabolite, 12-HETE, had a significant (2.24⯱â¯0.4) fold increase relative to control (Pâ¯=â¯0.0001) after Bonferroni Correction (BCF αâ¯=â¯0.003). We then determined the role of the 12/15-LO in LPS-induced acute kidney injury using genetic and pharmacological approaches. Treatment of LPS injected mice with the 12/15-LO inhibitor, baicalein, significantly reduced levels of renal injury and inflammation markers including urinary thiobarbituric acid reactive substance (TBARs), urinary monocyte chemoattractant protein-1 (MCP-1), renal interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Similarly, knocking-out of 12/15-LO reduced levels of renal inflammation and injury markers elicited by LPS injection. Next, we tested whether exogenous supplementation with docosahexaenoic acid (DHA) as a substrate would divert the role of 12/15-LO from being pro-inflammatory to anti-inflammatory via increased production of the anti-inflammatory metabolite. DHA treatment restored the decreased in plasma level of resolvin D2 (RvD2) and reduced renal injury in LPS-injected mice whereas DHA treatment failed to provide any synergistic effects in reducing renal injury in LPS injected 12/15-LO knock-out mice. The ability of RvD2 to protect kidney against LPS-induced renal injury was further confirmed by exogenous RvD2 which significantly reduced the elevation in renal injury in LPS injected mice. These data suggest a double-edged sword role of 12/15-LO in LPS-induced acute renal inflammation and injury, depending on the type of substrate available for its activity.
Assuntos
Injúria Renal Aguda/imunologia , Araquidonato 12-Lipoxigenase/imunologia , Araquidonato 15-Lipoxigenase/imunologia , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Injúria Renal Aguda/patologia , Animais , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BLRESUMO
Hepatocellular carcinoma (HCC) is still a leading cancer killer in the community. Molecular targeted therapy with celecoxib (CXB) has shown promising antitumor effects; however, its use may be limited due to serious side effects. Curcumin (CUR) has also shown beneficial effects against HCC. Then, it was aimed to investigate the effects of adding CUR to CXB on HCC HepG2 cells. HepG2 cells were treated with CXB and/or CUR at increasing concentrations to investigate synergistic drug interactions, as calculated combination index (CI). Combination treatment effects on cell viability and caspase-3 activation were assessed. The levels of Akt, nuclear factor-kappa B (NF-κB), prostaglandin E2 (PGE2), malondialdehyde (MDA), cyclin D1 (CD1), and vascular endothelial growth factor (VEGF) were also evaluated. CXB (3.13-100 µM) and/or CUR (1.25-40 µM) reduced HepG2 cell viability dose-dependently. Nevertheless, lower combined concentrations showed higher synergism (CI < 1) and higher CXB dose reduction index (DRI > 1). Also, the addition of CUR to CXB resulted in increased cytotoxicity and caspase-3 activation, as compared to CXB alone. In addition, the selected combination significantly reduced the levels of Akt, NF-κB, PGE2, MDA, CD1, and VEGF, as compared to either agent alone. In conclusion, CUR augmented the CXB-mediated antitumor effects in HepG2 cells through, at least in part, antiproliferative, antioxidant, and pro-apoptotic mechanisms. This may allow the further use of CXB at lower concentrations, combined with CUR, as a promising safer targeted strategy for HCC management.