No abstract

Hypoxia, the typical and conspicuous characteristic of most solid tumors, worsens the tumor invasiveness and metastasis. Here, we engineered a sequential ultrasound (US)/hypoxia-sensitive sonochemotherapeutic nanoprodrug by initially synthesizing the hypoxia-activated azo bond-containing camptothecin (CPT) prodrug (CPT2-Azo) and then immobilizing it into the mesopores of sonosensitizer-integrated metal organic frameworks (MOF NPs). Upon entering the hypoxic tumor microenvironment (TME), the structure of CPT2-Azo immobilized MOFs (denoted as MCA) was ruptured and the loaded nontoxic CPT2-Azo prodrug was released from the MOF NPs. Under US actuation, this sonochemotherapeutic nanoprodrug not only promoted sonosensitizer-mediated sonodynamic therapy (SDT) via the conversion of oxygen into cytotoxic reactive oxygen species (ROS) but also aggravated hypoxia in the TME by elevating oxygen consumption. The exacerbated hypoxia in turn served as a positive amplifier to boost the activation of CPT2-Azo, and the controllable release of toxic chemotherapeutic drug (CPT), and compensated the insufficient treatment efficacy of SDT. In vitro and in vivo evaluations confirmed that sequential SDT and tumor hypoxia-activated sonochemotherapy promoted the utmost of tumor hypoxia and thereby contributed to the augmented antitumor efficacy, resulting in conspicuous apoptotic cell death and noteworthy tumor suppression in vivo. Our work provides a distinctive insight into the exploitation of the hypoxia-activated sonochemotherapeutic nanoprodrug that utilizes the hypoxic condition in TME, a side effect of SDT, to initiate chemotherapy, thus causing a significantly augmented treatment outcome compared to conventional SDT.

Malignant gliomas (MGs) are among the most aggressive types of cancers in the human brain. Frequent tumor recurrence caused by a lack of effective therapeutic approaches results in a poor prognosis. Signal transducer and activator of transcription 3 (STAT3), an oncogenic protein, is constitutively activated in MGs and predicts a poor clinical outcome. STAT3 therefore is considered to be a promising target for the treatment of MGs. Cryptotanshinone (CTS), the main bioactive compound from the root of Salvia miltiorrhiza Bunge, has been reported to have various pharmacological effects. However, little is known about its function in MG cells. In this study, we evaluated the effect of CTS on the proliferation of human glioma cell lines (T98G and U87). Our results revealed that CTS significantly suppresses glioma cell proliferation. The phosphorylation of STAT3 Tyr705, but not Ser727, was inhibited by CTS, and STAT3 nuclear translocation was attenuated. Overexpression of constitutively active mutant STAT3C reversed the inhibitory effect of CTS, while knockdown STAT3 showed a similar inhibitory effect as CTS treatment. Following the downregulation of STAT3-regulated proteins cyclinD1 and survivin, cell cycle progression significantly arrested in G1/G0 phase. These results indicate that CTS may be a potential antiproliferation agent for the treatment of MGs and that its mechanism may be related to the inhibition of STAT3 signaling.

Malignant gliomas (MGs) are one of the most common primary brain cancers in adults with a high mortality rate and relapse rate. Thus, finding better effective approaches to treat MGs has become very urgent. Here, we studied the effects of cryptotanshinone (CTS) on MGs in vitro and in vivo, and explored the underlying mechanisms. Effects of CTS in vitro on cell proliferation, cycle, migration and invasion were evaluated. The activation of JAK/STATs signaling was detected by western blot and immunofluorescenc staining. SHP-2 inhibitor or SiRNA were used to determine the involvement of SHP-2. The in vivo anti-MGs activity of CTS was studied with nude mice bearing intracerebral U87 xenografts. Our results revealed that CTS significantly inhibited the proliferation of MGs in vitro via inhibiting STAT3 signal pathway. The cell cycle was arrested at G0/G1 phase. Although CTS did not change the expression of total SHP-2 protein, the tyrosine phosphatase activity of SHP-2 protein was increased by CTS treatment in a dose-dependent manner in vivo and in vitro. SHP-2 inhibitor or SiRNA could reverse the inhibitory effect of CTS on phosphorylation of STAT3 Tyr705. In vivo study also showed that CTS inhibited the intracranial tumor growth and extended survival of nude mice bearing intracerebral U87 xenografts, confirming an inhibitory effect of CTS on MGs. Our results indicated CTS may be a potential therapeutic agent for MGs. The inhibitory action of CTS is largely attributed to the inhibition of STAT3 Tyr705 phosphorylation with a novel mechanism of upregulating the tyrosine phosphatase activity of SHP-2 protein.

Peroxisome proliferator-activated receptor alpha (PPARα) has been implicated in the pathogenesis of cardiac hypertrophy, although its mechanism of action remains largely unknown. To determine the effect of PPARα activation on endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy and explore its molecular mechanisms, we evaluated the interaction of PPARα with nuclear factor of activated T-cells c4 (NFATc4) in nuclei of cardiomyocytes from neonatal rats in primary culture. In ET-1-stimulated cardiomyocytes, data from electrophoretic mobility-shift assays (EMSA) and co-immunoprecipitation (co-IP) revealed that fenofibrate (Fen), a PPARα activator, in a concentration-dependent manner, enhanced the association of NFATc4 with PPARα and decreased its interaction with GATA-4, in promoter complexes involved in activation of the rat brain natriuretic peptide (rBNP) gene. Effects of PPARα overexpression were similar to those of its activation by Fen. PPARα depletion by small interfering RNA abolished inhibitory effects of Fen on NFATc4 binding to GATA-4 and the rBNP DNA. Quantitative RT-PCR and confocal microscopy confirmed inhibitory effects of PPARα activation on elevation of rBNP mRNA levels and ET-1-induced cardiomyocyte hypertrophy. Our results suggest that activated PPARα can compete with GATA-4 binding to NFATc4, thereby decreasing transactivation of NFATc4, and interfering with ET-1 induced cardiomyocyte hypertrophy.

No abstract

Malignant gliomas represent one of the most aggressive types of cancers and their recurrence is closely linked to acquired therapeutic resistance. A combination of chemotherapy is considered a promising therapeutic model in overcoming therapeutic resistance and enhancing treatment efficacy. Herein, we show by colony formation, Hochest 33342 and TUNEL staining, as well as by flow cytometric analysis, that LY294002, a specific phosphatidylinositide-3-kinase (PI3K) inhibitor, enhanced significantly the sensitization of a traditional cytotoxic chemotherapeutic agent, tamoxifen-induced apoptosis in C6 glioma cells. Activation of PI3K signaling pathway by IGF-1 protected U251 cells from apoptosis induced by combination treatment of LY294002 and tamoxifen. Interference of PI3K signaling pathway by PI3K subunit P85 siRNA enhanced the sensitization of U251 glioma cells to tamoxifen -induced apoptosis. By Western blotting, we found that combination treatment showed lower levels of phosphorylated AktSer473 and GSK-3βSer9 than a single treatment of LY294002. Further, we showed a significant decrease of nuclear β-catenin by combination treatment. In response to the inhibition of β-catenin signaling, mRNA and protein levels of Survivin and the other three antiapoptotic genes Bcl-2, Bcl-xL, and Mcl-1 were significantly decreased by combination treatment. Our results indicated that the synergistic cytotoxic effect of LY294002 and tamoxifen is achieved by the inhibition of GSK-3β/β-catenin signaling pathway.

Qualitative and quantitative CEUS analyses are helpful in the differential diagnosis of ccRCCs, EAMLs, and TAMLs.