Ovarian cancer is one of the most lethal cancers in female reproductive system due to heterogeneity and lack of effective treatment. Targeting aerobic glycolysis, a predominant energy metabolism of cancer cells has been recognized a novel strategy to overcome cancer cell growth. However, the capability of cancer cells to undergo metabolic reprogramming guarantees their survival even when glycolysis is inhibited. Here in this study, we have shown that Cryptotanshinone (CT), a lipid-soluble bioactive anticancer molecule of Salvia miltiorrhiza, inhibits both glycolysis and oxidative phosphorylation (OXPHOS) in ovarian cancer cells leading to growth suppression and apoptosis induction. Our mechanistic study revealed that CT decreased glucose uptake and lactate production, and inhibited the kinase activity of LDHA and HK2. The molecular docking study showed that CT could directly bind with GLUT1, LDHA, HK2, PKM2 and complex-1. The immunoblotting data showed that CT decreased the expression of aberrantly activated glycolytic proteins includingGLUT1, LDHA, HK2, and PKM2. Besides, we found that CT inhibited mitochondrial ComplexⅠ activity, decreased the ratio of NAD⁺/NADH, and suppressed the generation of ATP and induced activation of AMPK, which controls energy-reducing processes. These in vitro findings were further validated using xenograft model. The findings of in vivo studies were in line with in vitro studies. Taken together, CT effectively suppressed glycolysis and OXPHOS, inhibited growth and induced apoptosis in ovarian cancer cells both in vitro and in vivo study models.

Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC). During TACE, chemotherapeutic agents are locally infused into the tumor and simultaneously cause hypoxia in tumor cells. Importantly, the poor effect of TACE in some HCC patients has been shown to be related to dysregulated expression of hypoxia-related genes (HRGs). Therefore, we identified 33 HRGs associated with TACE (HRGTs) by differential analysis and characterized the mutational landscape of HRGTs. Among 586 HCC patients, two molecular subtypes reflecting survival status were identified by consistent clustering analysis based on 24 prognosis-associated HRGs. Comparing the transcriptomic difference of the above molecular subtypes, three molecular subtypes that could reflect changes in the immune microenvironment were then identified. Ultimately, four HRGTs (CTSO, MMP1, SPP1, TPX2) were identified based on machine learning approachs. Importantly, risk assessment can be performed for each patient by these genes. Based on the parameters of the risk model, we determined that high-risk patients have a more active immune microenvironment, indicating “hot tumor” status. And the Tumor Immune Dysfunction and Exclusion (TIDE), the Cancer Immunome Atlas (TCIA), and Genome of Drug Sensitivity in Cancer (GDSC) databases further demonstrated that high-risk patients have a positive response to immunotherapy and have lower IC50 values for drugs targeting cell cycle, PI3K/mTOR, WNT, and RTK related signaling pathways. Finally, single-cell level analysis revealed significant overexpression of CTSO, MMP1, SPP1, and TPX2 in malignant cell after PD-L1/CTLA-4 treatment. In conclusion, Onco-Multi-OMICS analysis showed that HRGs are potential biomarkers for patients with refractory TACE, and it provides a novel immunological perspective for developing personalized therapies.

Realgar- and cinnabar-containing AnGongNiuHuang Pill (AGNHP) is widely used for treating encephalopathy syndrome. However, it raises great safety concerns due to the adverse effects reported by arsenic or mercury poisoning. Although AGNHP has been generally recognized, little is known about the metabolism of arsenic and mercury and their resulting potential health risk in vivo. Thus, comparative pharmacokinetics and urinary excretion of arsenic and mercury were conducted in rats after oral administration of realgar, cinnabar and AGNHP, respectively. The contents of arsenic and mercury in rat blood and urine were determined by hydride-generation atomic fluorescence spectrometry (HG-AFS) after wet digestion. AGNHP significantly reduced the absorption of arsenic in blood and promoted urinary arsenic excretion. Whereas, it increased the blood mercury absorption and reduced urinary mercury excretion. No significant toxicity was observed in the clinical dose range of AGNHP. However, excessive exposure to arsenic and mercury may still pose risks especially by long-term or excessive medication. The results are helpful for the rational clinical applications of realgar- and cinnabar-containing TCMs.

Cryptotanshinone (CT), an active component of the traditional Chinese medicine Salvia miltiorrhiza Bunge, exhibits a wide range of biological and pharmacological activities. Although the anticancer activity of CT is well known, the knowledge of its effect on the regulation of cancer cell metabolism is relatively new. The present study investigated the anticancer mechanism of CT in ovarian cancer with a focus on cancer metabolism. CCK8 assays, apoptosis assays, and cell cycle assays were conducted to reveal the growth-suppressive effect of CT on ovarian cancer A2780 cells. To explore the potential underlying mechanisms of CT, the changes in endogenous metabolites in A2780 cells before and after CT intervention were investigated using the gas chromatography–mass spectrometry (GC-MS) approach. A total of 28 important potential biomarkers underwent significant changes, mainly involving aminoacyl-tRNA biosynthesis, energy metabolism, and other pathways. Changes in the ATP and amino acid contents were verified with in vitro and in vivo experiments. Our results indicate that CT may exert an anti-ovarian cancer effect by inhibiting ATP production, promoting the protein catabolic process, and inhibiting protein synthesis, which may lead to cell cycle arrest and apoptosis.