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ATP-binding cassette (ABC) transporter C10 (ABCC10), also named multidrug resistance protein 7 (MRP7), is a member of ABC transporter superfamily and has been revealed to transport a wide range of chemotherapeutic agents including taxanes, epothilone B, Vinca alkaloids, and anthracyclines. In our previous study, a 5-cyano-6-phenylpyrimidin derivative CP55 was synthesized and found significantly reversal effect of multidrug resistance (MDR) mediated by ABCB1. In this study, we found CP55 also efficiently reversed MDR mediated by ABCC10. Our in vitro study showed that co-treatment with CP55 significantly increased the efficacy of ABCC10-substrate anticancer drugs in MDR cells overexpressing ABCC10. Furthermore, we showed that treatment with CP55 increased the intracellular accumulation of [3H]-labeled anticancer drugs and in-turn decreasing drug efflux by inhibiting the transport activity, without altering ABCC10 protein ex-pression level or cellular localization. Potential CP55-ABCC10 interactions were predicted via docking analysis using human ABCC10 homology model and obtained high docking score. Therefore, CP55 represents a promising therapeutic agent in the combinational treatment of chemo-resistant cancer related to ABCC10. Proposed mechanism of CP55 in inhibiting the multidrug resistance mediated by ABCC10 in cancer cells. [Display omitted] • Multidrug resistance (MDR) in cancer is one of the major obstacles in chemotherapy. • ABCC10 mediates resistance to wide spectrum of chemotherapeutic agents, but only limited number of studies are available. • Overexpression of ABCC10 has been linked to various types of cancers including colorectal, gastric and lung cancer. • CP55 is a potent ABCC10 inhibitor which enhances the anticancer drug sensitivity in ABCC10-overexpression MDR cells. [ABSTRACT FROM AUTHOR]

• Three new alkaloids, iizukines C−E (1 − 3), were identified from Aspergillus iizukae. • Compound 1 is the first aspochalasin with a 1,2,4−triazole functionality. • Compound 1 showed cytotoxicity to HL−60 and A549 (IC 50 3.8 and 7.2 μM, respectively). • Compound 3 gave a pair of NMR signals attributed to conformational isomers in CDCl 3. Three new alkaloids, iizukines C−E (1 – 3), including two aspochalasins (1 and 2), and one brasiliamide derivative (3), along with two known aspochalasins, rosellichalasin (4) and cytochalasin Z17 (5), were isolated from the culture of Aspergillus iizukae. Compound 1 was the first aspochalasin uniquely featuring a 1,2,4-triazole functionality, and 3 showed a pair of NMR signals in CDCl 3 with a ratio of about 2:1 due to the existence of conformational isomers. Their structures were determined by extensive spectroscopic analyses and single-crystal X-ray diffractions. In particular, the 1,2,4-triazole moiety in 1 was assigned on the basis of extremely valuable 1H-15N HMBC spectrum. Compound 1 exhibited cytotoxic effect towards HL-60 and A549 cell lines with IC 50 values of 3.8 and 7.2 μM, respectively. [ABSTRACT FROM AUTHOR]

[Display omitted] • EZH2 is a potential target to inhibit the development of fibrosis. • TGF-β1 closely related to EZH2 may be involved in the processes of multiple fibrosis. • EZH2 inhibitors alone or in combination with other agents have shown promising prospects in the treatment of fibrotic diseases. Fibrosis affects the function of many organs and tissues, and its persistent development can lead to tissue sclerosis and cancer, even leading to death further. Recent studies suggested that enhancer of zeste homolog 2 (EZH2), a major regulator of epigenetic repression, played an important role in the occurrence and development of fibrosis through gene silencing or transcriptional activation. As the most studied and powerful pro-fibrotic cytokine closely related to EZH2, TGF-β1 was primarily involved in the regulation of fibrosis along with the typical Smads and non-Smads signaling pathways. In addition, EZH2 inhibitors demonstrated inhibitory effects in several types of fibrosis. This review summarized the relationship underlying the action of EZH2, TGF-β1/Smads, and TGF-β1/non-Smads with fibrosis and described the research progress of EZH2 inhibitors in the treatment of fibrosis. [ABSTRACT FROM AUTHOR]

Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC 50 = 0.336 ± 0.003 μM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti-ESCC drug discovery. [ABSTRACT FROM AUTHOR]

[Display omitted] • The specific crystallography structure, compositions and functions of HDAC6 were reviewed. • The relation of HDAC6 with tumor immune diseases was summarized. • HDAC6 inhibitors in combination with antitumor immunomodulatory agents were discussed. Tumor immunotherapy is currently subject of intense scientific and clinical developments. In previous decade, therapists used natural immune system from the human body to treat several diseases. Although tumor immune disease is a big challenge, combinatorial therapeutic strategy has been succeeded to show the clinical significance. In this context, we discuss the HDAC6 and tumor immune diseases relationship. Also, we summarized the current state of knowledge that based on the combination treatments of the HDAC6 inhibitors (HDAC6is) with antitumor immunomodulatory agents. We observed that, the combination therapies slow down the tumor immune diseases by blocking the aggresome and proteasome pathway. The combination therapy was able to reduce M2 macrophage and increasing PD-L1 blockade sensitivity. Most importantly, multiple combinations of HDAC6is with other agents may consider as potential strategies to treat tumor immune diseases, by reducing the side effects and improve efficacy for the future clinical development. [ABSTRACT FROM AUTHOR]

• A pharmacophore fusion strategy was adopted to optimizenatural product gramin. • Terminal alkyne was vital for enhancing the antiproliferative activity. • 16h could induce cell apoptosis and inhibit metastasis ability of MGC803 cells. Gramine is a natural indole alkaloid with a wide range of biological activities, but its anti-gastric cancer activity is poor. Herein, a pharmacophore fusion strategy was adopted to design and synthesize a new series of indole-azole hybrids on the structural basis of gramine. Based on our previous studies, different nitrogen-containing five-membered heterocyclic rings and terminal alkyne group were introduced into the indole-based scaffold to investigate their effect on improving the anti-gastric cancer activity of gramine derivatives. Structure-activity relationship (SAR) studies highlighted the role played by terminal alkyne in enhancing the inhibitory effect, and compound 16h displayed the best antiproliferative activity against gastric cancer MGC803 cells with IC 50 value of 3.74 μM. Further investigations displayed compound 16h could induce mitochondria-mediated apoptosis, and caused cell cycle arrest at G2/M phase. Besides, compound 16h could inhibit the metastasis ability of MGC803 cells. Our studies may provide a new strategy for structural optimization of gramine to enhance anti-gastric cancer activity, and provide a potential candidate for the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]