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Background: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. Our study intended to assess the combination of dasatinib and irinotecan against HCC and made an effort to develop a potential medical choice for advanced HCC patients., Methods: We used SRB colorimetric assay and clonogenic assay to assess antitumour effect in vitro and HCC xenograft model to assess antitumour effect in vivo. We applied flow cytometry and western blotting to explore the mechanism of the combined therapy. Knockdown and overexpression of PLK1 are also applied for validation., Results: We confirmed that dasatinib has synergistic effect with irinotecan (or SN38) on HCC both in vitro and in vivo. The effect is due to arisen apoptosis rate of HCC cells that is accompanied by mitochondria dysfunction. The enhanced antitumour efficacy of SN38 could be explained by additional inhibition of PLK1, which is triggered by dasatinib. Unlike existed PLK1 inhibitors, dasatinib does not inhibit PLK1 activity in a direct way. Instead, we found that dasatinib reduces PLK1 level by interfering with its protein synthesis progress. We validated that this kind of downregulation of PLK1 level has a key role in the synergistic effect of the two agents., Conclusions: Dasatinib is able to reinforce the anti-HCC efficacy of irinotecan/SN38 by downregulation of PLK1 synthesis. The combination of the two agents might be a potential medical choice for HCC therapy.

Background: Chemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more effective and less toxic., Methods: MTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis., Results: We found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model., Conclusions: Our data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies.

Background: Chemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more effective and less toxic. Methods: MTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis. Results: We found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model. Conclusions: Our data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies. [ABSTRACT FROM AUTHOR]

Through bioassay-guided fractionation of the extracts from the aerial parts of the Chinese herb Hypericum japonicum Thunb. Murray, Isojacareubin (ISJ) was characterized as a potent antibacterial compound against the clinical methicillin-resistant Staphylococcus aureus (MRSA). The broth microdilution assay was used to determine the minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of ISJ alone. The results showed that its MICs/MBCs ranged from 4/16 to 16/64 µg/mL, with the concentrations required to inhibit or kill 50% of the strains (MIC50/MBC50) at 8/16 µg/mL. Synergistic evaluations of this compound with four conventional antibacterial agents representing different types were performed by the chequerboard and time-kill tests. The chequerboard method showed significant synergy effects when ISJ was combined with Ceftazidime (CAZ), Levofloxacin (LEV) and Ampicillin (AMP), with the values of 50% of the fractional inhibitory concentration indices (FICI50) at 0.25, 0.37 and 0.37, respectively. Combined bactericidal activities were also observed in the time-kill dynamic assay. The results showed the ability of ISJ to reduce MRSA viable counts by log10CFU/mL at 24 h of incubation at a concentration of 1 × MIC were 1.5 (LEV, additivity), 0.92 (CAZ, indifference) and 0.82 (AMP, indifference), respectively. These in vitro anti-MRSA activities of ISJ alone and its synergy with conventional antibacterial agents demonstrated that ISJ enhanced their efficacy, which is of potential use for single and combinatory therapy of patients infected with MRSA. [ABSTRACT FROM AUTHOR]

Cisplatin is a widely used chemotherapy drug that is first-line therapy for a variety of tumors. Unfortunately, its adverse effects on various normal tissues and organs, especially nephrotoxicity, threaten the life of patients. Although the mechanism of cisplatin nephrotoxicity has been confirmed to be related to oxidative stress, apoptosis of renal tubular epithelial cells and inflammatory response, there is no effective prevention strategy in the clinic. Here, we found that bisdemethoxycurcumin (BDMC), a natural compound, can significantly attenuates cisplatin-induced apoptosis of renal tubular epithelial cells in vitro at the concentration of 5–20 μM and has a significant protective effect on cisplatin-induced kidney injury in mice at the dose of 50 mg/kg. Mechanistically, BDMC attenuates cisplatin-induced apoptosis of renal tubular epithelial cells by inhibiting cisplatin-induced up-regulation of p53. Meanwhile, BDMC counteracts oxidative stress by inhibiting cisplatin-induced down-regulation of nuclear factor erythroid-2-related factor 2 (Nrf2). BDMC also significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) proteins, as well as the expression and translocation of the p65 subunit of nuclear factor-κB (NF-κB p65) into the nucleus, all of which were increased in the kidney by cisplatin treatment. Collectively, BDMC might be an effective prevention strategy which could against cisplatin-induced nephrotoxicity, and our research may shed a new light on treatment of drug toxicity. • Bisdemethoxycurcumin could alleviate cisplatin-induced renal toxicity in vitro. • Bisdemethoxycurcumin can significantly alleviate cisplatin nephrotoxicity in vivo. • Bisdemethoxycurcumin relieves cisplatin nephrotoxicity through anti-apoptotic, anti-oxidant and anti-inflammatory effects. • Bisdemethoxycurcumin has synergistic anti-tumor effect with cisplatin. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of quinolinone-based adenosine A2B receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A2B antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1nM) and an IL-8 release assay (0.4nM). [ABSTRACT FROM AUTHOR]