Synergy最新文献

Background

Multidrug resistance (MDR) to known chemotherapeutic agents is increasing while the development of new drugs is lacking behind. Combination therapies might increase the development of effective treatment. Anticancer properties of C. sativa L. have been extensively studied against various cancer cell lines but research on its effectiveness on MDR in cancer is less documented.

Aim

To determine the potential resistant reversal of the cytostatic drug doxorubicin by C. sativa L. extracts through combination studies.

Method

The cytotoxic effect of the different C. sativa L. extracts was assessed against a panel of human colon cancer cells (HT-29, Caco-2, HCT-15, LS513) and normal colon cells (CCD-18Co) by MTT assay. Drug-extract combination studies were performed on HCT-15 and LS513 MDR cells.

Results

DCM: methanol- and H₂O extracts moderately inhibited the growth in HCT-15 and LS513 cells (IC₅₀: 20–100 μg/ml). DCM- and H₂O extracts potently inhibited HT-29 cell growth. Higher concentrations (100 μg/ml) of the hexane- and DCM- extracts slightly stimulated growth in Caco-2 cells. All the C. sativa L. extracts were more cytotoxic towards the cancerous cells than towards the normal colon cells. Combination studies between doxorubicin and the C. sativa L. extracts revealed synergistic growth inhibitory effects (CI < 1). The sensitivity to doxorubicin increased in HCT-15 and LS513 cells by 2.08- to 74.07-fold and 2.21- to 300.7-fold, respectively, compared to verapamil which improved it by 1.41-fold and 0.05-fold, respectively.

Conclusion

C. sativa L. extracts possess direct selective cytotoxic effect on colon cells and have a potential to reverse doxorubicin resistance.

Triple Negative Breast Cancer (TNBC) treatment is more challenging than other subtypes of breast malignancy and due to the lack of markers for the molecularly targeted therapies (ER, PR, and HER-2/Neu), the conventional chemotherapeutic agents are still the mainstay of the therapeutic protocols of its patients. Unfortunately, the initial good response to the chemotherapy eventually turns into a refractory drug-resistance, therefore; more efficient therapeutic regimens are urgently required. Here, we examined the single and combined cytotoxicity of PU-H71, Dehydroepiandrosterone, Berberine, and Sorafenib on the MDA-MB-231 triple negative breast cancer cells after 48 h incubation period through the neutral red uptake assay. Based on Median Effect Equation (Chou), Combination Index Theorem and Dose Reduction Index Equation (Chou-Talalay), we tested six binary combinations and four ternary ones to define and quantify their pharmaco-dynamic interactions (synergism, antagonism or additivity). The highest-to-lowest order of potency of a single drug treatment was PU-H71 > Sorafenib > Berberine > Dehydroepiandrosterone. At fractional affected level (fa) ≥ 0.90, almost all the actual and computer-simulated combinations exerted synergistic effects, where (PU-H71 plus Sorafenib), (Berberine plus Sorafenib) and (PU-H71 plus Berberine plus Sorafenib) were the strongest synergistic combinations with CI value < 0.30. Based on our in vitro combination results, we suggest subsequent downstream investigations to understand the molecular mechanisms of such promising synergistic combinations. Additionally, we recommend the application of such combinations on TNBC-xenografted animal models to effectively establish the gono-go decision of the further application in clinical settings.

Under hypoxic conditions, NO plays an important role in regulating O₂ delivery by controlling local blood vessel relaxation. NO is primarily produced by endothelial NO synthase (eNOS), which is reportedly phosphorylated at Ser⁶³⁵ and thereby activated under conditions of fluid shear stress and O₂ concentration. The aim of this work was to investigate the effects of fluid shear stress and O₂ concentration on the phosphorylation of eNOS at Ser⁶³⁵. Bovine aortic endothelial cells were exposed to hypoxia only, a combination of shear stress and hyperoxia, and a combination of shear stress and hypoxia at various time points. Hypoxia did not increase phosphorylation significantly at 15 min but induced a gradual increase to 1.94-fold over 180 min. Under simultaneous exposures to shear stress and hyperoxia, eNOS phosphorylation was detected after 15-min and was 2.75-fold higher than the initial condition at the 60-min time point. In contrast, under a combination of shear stress and hypoxia, eNOS phosphorylation was increased to 2.44-fold at 60 min. However, although phosphorylation levels under these conditions were higher than those after hypoxia only at all time points, they were lower than those after a combination of shear stress and hyperoxia. Our results indicate that hyperoxia and shear stress additively stimulate phosphorylation of eNOS at Ser⁶³⁵ and suggest a moderating role of hypoxia.

Decades back, there were reports on the pathogenic association between diabetes mellitus (DM) and osteoarthritis (OA). Moreover, it was recently reported that in the presence of DM, OA worsens glycaemic control, and that various symptoms of these disease conditions offset each other. Therefore, the present study investigated the effects of salmon calcitonin (Sct) and/or omega–3 fatty acids (N-3: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); EPA/DHA ratio = 3/2) on known biochemical markers in diabetic-knee osteoarthritic rats. Diabetes was induced by the administration of streptozotocin (65 mg/kg) and nicotinamide (110 mg/kg), while, knee OA was induced by the intra-articular injection of 4 mg of sodium monoiodoacetate. Thereafter, N-3 were administered at 200 mg/kg/day, while Sct was administered at 2.5 and 5.0 IU/kg/day for four weeks. The results showed that the induced diabetic-osteoarthritic condition featured imbalances of lipid metabolism, pro-inflammatory and hyperglycaemic responses. After N-3 administration, there were significant hypercalcaemic, hypoglycaemic, and insulin releasing effects. Moreover, N-3 significantly elevated glycogenesis in the hepatic tissue and nitric oxide synthesis. However, Sct significantly contradicted all these effects in a dose-dependent and non-dose dependent measures. Nevertheless, both therapies demonstrated non-additive effects on cortisol, interleukin-6, lipid profile, and uric acid. In conclusion, the co-administration of Sct and N-3, and not the single therapy, could be preferably used in the management of diabetic-osteoarthritic state.

Recent publication evidenced about rationality and efficacy of combinatory therapy of antibiotic resistance, diabetes, obesity, cancer, viral infections, inflammatory bowel disease, etc. The combination of nutrients and pharmaceuticals has a good chance of contributing to a modern strategy of multi-target drug discovery. Different approaches and methods for the investigation of combinatory modes of action can be roughly classified into: in vitro, in vivo, in silico and in clinic. There is no true "gold standard" method that can be used uniformly to detect and quantify combinatory modes of action in pharmacology. Different methods of testing for synergism can sometimes produce different conclusions for the same combination. Great efforts in the translation of in vitro and in vivo results into clinical benefits of combinatory modes of action of nutrients and pharmaceuticals are compulsory.