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Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (k inact/K i = 4.17 × 103 M-1 s-1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor. [ABSTRACT FROM AUTHOR]

Leaf extract of Ginkgo biloba (GBE) is increasingly used as a herbal medicine for the treatment of neurodegenerative, cardiovascular and cerebrovascular diseases. Several studies have demonstrated many protective effects of GBE in neurons, the endothelium and liver. In this study, we investigated the molecular mechanisms underlying the effects of GBE in disorders induced by long-term exposure to a high-fat diet (HFD). Rats were fed an HFD with or without the GBE product GBE50 for 19 weeks. We found that GBE50 reduced the development of fatty liver induced by an HFD and inhibited the commonly observed elevation of serum cholesterol and lactate dehydrogenase levels. Transcriptome profiling analysis showed that several genes were modulated by GBE50 in liver, including those involved in lipid metabolism, carbohydrate metabolism, vascular constriction, ion transportation, neuronal systems and drug metabolism. Notably, a number of genes coding for proteins involved in cholesterol metabolism were repressed, and some were upregulated. Fatty acid biosynthesis appeared to be repressed, whereas fatty acid metabolism appeared to be enhanced. In conclusion, using transcriptome profiling analysis, we demonstrated the molecular basis for the pleiotropic effects of GBE50, particularly those involved in lipid metabolism. This study provided new clues for further pharmacological study of GBEs. [ABSTRACT FROM AUTHOR]

Background: Stimulator of interferon genes (STING) has emerged as a crucial and promising target in tumor immunotherapy in recent years. Its agonists play a vital role in activating both innate and adaptive immune responses to combat cancer. Currently, STING agonists are primarily administered through intratumoral or intravenous injection, with only a few could be administered by orally. Therefore, orally available STING agonists are urgently needed to be developed. Approach and results: Based on previous structure-activity relationship (SAR) studies, we made a structure modification to MSA-2 by replacing the carbonyl group with a difluoromethylene to get a new compound 202 (C202) that exhibited better plasma exposure and oral bioavailability than MSA-2. Thus, we conducted extensive pharmacological evaluations to understand its effects. C202 demonstrated the ability to activate various human STING isoforms and murine STING protein, showcasing a potent and specific activation of the STING signalling pathway at cellular level. In diverse immunocompetent mouse models representing both ‘cold’ and ‘hot’ tumors, C202, whether administered intratumorally or orally, displayed broad-spectrum anti-tumor activity. Encouragingly, it induced complete tumor regression in several tumor models of mice and stimulated immune memory effects, contributing to long-term immune response against cancer. Additionally, our investigations into the impact of C202 on the tumor microenvironment found that it enhanced the anti-tumor response of both innate and adaptive immune systems, bolstering the immune-mediated fight against tumors. Furthermore, we made an intriguing observation regarding C202’s synergistic effects. It was found to enhance the anti-tumor activity of chemotherapy drug gemcitabine and the angiogenesis inhibitor AL3810, which provide potential combination therapies in future translational studies. Conclusions: Our research highlights C202 as a novel STING agonist with durable anti-tumor activity that can be administered orally, presenting a promising candidate for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) play fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. Although HDACs are recognized to be closely related to cancer development and altered expression of certain HDACs is observed in tumor samples, the arcane characters of HDACs in tumorigenesis have not been fully illustrated. Herein, we report that HDAC7 is a crucial player in cancer cell proliferation. Knockdown of HDAC7 resulted in significant G/S arrest in different cancer cell lines. Subsequent investigations indicated that HDAC7 silencing blocked cell cycle progression through suppressing c-Myc expression and increasing p21 and p27 protein levels. The ectopic expression of c-Myc in turn antagonized the cell cycle arrest and repressed the elevation of p21 and p27 in HDAC7 silencing setting. Of note, HDAC7 deficiency was further identified to induce cellular senescence program, which was also reversed by c-Myc re-expression. Further chromatin immunoprecipitation assays indicated that HDAC7 directly binds with c-Myc gene and HDAC7 silencing decreased c-Myc mRNA level via reducing histone H3/H4 acetylation and repressing the association of RNA polymerase II (RNAP II) with c-Myc gene. Taken together, our findings highlight for the first time an unrecognized link between HDAC7 and c-Myc and offer a novel mechanistic insight into the contribution of HDAC7 to tumor progression. [ABSTRACT FROM AUTHOR]

Glycolytic enzymes are known to play pivotal roles in cancer cell survival, yet their molecular mechanisms remain poorly understood. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that coordinates glycolysis, pentose phosphate pathway, and serine biosynthesis in cancer cells. Herein, we report that PGAM1 is required for homologous recombination (HR) repair of DNA double-strand breaks (DSBs) caused by DNA-damaging agents. Mechanistically, PGAM1 facilitates DSB end resection by regulating the stability of CTBP-interacting protein (CtIP). Knockdown of PGAM1 in cancer cells accelerates CtIP degradation through deprivation of the intracellular deoxyribonucleotide triphosphate pool and associated activation of the p53/p73 pathway. Enzymatic inhibition of PGAM1 decreases CtIP protein levels, impairs HR repair, and hence sensitizes BRCA1/2-proficient breast cancer to poly(ADP-ribose) polymerase (PARP) inhibitors. Together, this study identifies a metabolically dependent function of PGAM1 in promoting HR repair and reveals a potential therapeutic opportunity for PGAM1 inhibitors in combination with PARP inhibitors. [ABSTRACT FROM AUTHOR]

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous- sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10-4), increased frequency of nonsynonymous SSNVs in Pan- Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10-17); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers. [ABSTRACT FROM AUTHOR]

Curcumin, a principal component of turmeric (Curcuma longa), has potential therapeutic activities against breast cancer through multiple signaling pathways. Increasing evidence indicates that curcumin reverses chemo-resistance and sensitizes cancer cells to chemotherapy and targeted therapy in breast cancer. To date, few studies have explored its potential antiproliferation effects and resistance reversal in antiestrogen-resistant breast cancer. In this study, we therefore investigated the efficacy of curcumin alone and in combination with tamoxifen in the established antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. We discovered that curcumin treatment displayed anti-proliferative and pro-apoptotic activities and induced cell cycle arrest at G2/M phase. Of note, the combination of curcumin and tamoxifen resulted in a synergistic survival inhibition in MCF-7/LCC2 and MCF-7/LCC9 cells. Moreover, we found that curcumin targeted multiple signals involved in growth maintenance and resistance acquisition in endocrine resistant cells. In our cell models, curcumin could suppress expression of pro-growth and anti-apoptosis molecules, induce inactivation of NF-κB, Src and Akt/mTOR pathways and downregulate the key epigenetic modifier EZH2. The above findings suggested that curcumin alone and combinations of curcumin with endocrine therapy may be of therapeutic benefit for endocrine-resistant breast cancer. [ABSTRACT FROM AUTHOR]