biochanin-a and Neoplasms

LSD1 was significantly over-expressed in several cancer types, and its aberrant overexpression was revealed to play a crucial role in the initiation and progression of cancer. Several LSD1 inhibitors that were discovered and developed so far were found to be effective in attenuating tumor growth in both in vivo and in vitro studies. However, the major challenge associated with the development of cancer therapies is personalized treatment. Therefore, it is essential to look in detail at how LSD1 plays its part in carcinogenesis and whether there are any different expression levels of LSD1 in different tumors. Here in this review, fresh insight into a list of function correlated LSD1 binding proteins are provided, and we tried to figure out the role of LSD1 in different cancer types, including hematological malignancies and solid tumors. A critical description of mutation preference for LSD1 in different tumors was also discussed. Recent research findings clearly showed that the abrogation of LSD1 demethylase activity via LSD1 inhibitors markedly reduced the growth of cancer cells. But there are still many ambiguities regarding the role of LSD1 in different cancers. Therefore, targeting LSD1 for treating different cancers is still reductionist, and many challenges need to be met to improve the therapeutic outcomes of LSD1 inhibitors.

Topics: Carcinogenesis; Histone Demethylases; Humans; Neoplasms

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising target for the discovery of specific inhibitors as antitumor drugs. Based on the source of compounds, all LSD1 inhibitors in this review are divided into two categories: natural LSD1 inhibitors and synthetic LSD1 inhibitors. This review highlights the research progress of LSD1 inhibitors with the potential to treat cancer covering articles published in 2020. Design strategies, structure-activity relationships, co-crystal structure analysis and action mechanisms are also highlighted.

Topics: Antineoplastic Agents, Phytogenic; Enzyme Inhibitors; Histone Demethylases; Humans; Molecular Structure; Neoplasms

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

AKR1B10 is an NADPH-dependent reductase that plays an important function in several physiological reactions such as the conversion of retinal to retinol, reduction of isoprenyl aldehydes, and biotransformation of procarcinogens and drugs. A growing body of evidence points to the important role of the enzyme in the development of several types of cancer (e.g., breast, hepatocellular), in which it is highly overexpressed. AKR1B10 is regarded as a therapeutic target for the treatment of these diseases, and potent and specific inhibitors may be promising therapeutic agents. Several inhibitors of AKR1B10 have been described, but the area of natural plant products has been investigated sparingly. In the present study almost 40 diverse phenolic compounds and alkaloids were examined for their ability to inhibit the recombinant AKR1B10 enzyme. The most potent inhibitors-apigenin, luteolin, and 7-hydroxyflavone-were further characterized in terms of IC50, selectivity, and mode of action. Molecular docking studies were also conducted, which identified putative binding residues important for the interaction. In addition, cellular studies demonstrated a significant inhibition of the AKR1B10-mediated reduction of daunorubicin in intact cells by these inhibitors without a considerable cytotoxic effect. Although these compounds are moderately potent and selective inhibitors of AKR1B10, they constitute a new structural type of AKR1B10 inhibitor and may serve as a template for the development of better inhibitors.

Topics: Aldehyde Reductase; Aldo-Keto Reductases; Apigenin; Daunorubicin; Enzyme Inhibitors; Flavones; Flavonoids; HCT116 Cells; Humans; Luteolin; Molecular Conformation; Molecular Structure; Neoplasms

Several classes of flavonoids [flavanoids (1-10), flavonol (11), isoflavones (12-18), isoflavanones (19-22), isoflavans (23-26), chalcones (27-30), auronol (31), pterocarpans (32-37), 2-arylbenzofuran (38), and neoflavonoid (39)] and lignans (40-42) isolated from the MeOH extract of Brazilian red propolis were investigated for their cytotoxic activity against a panel of six different cancer cell lines including murine colon 26-L5 carcinoma, murine B16-BL6 melanoma, murine Lewis lung carcinoma, human lung A549 adenocarcinoma, human cervix HeLa adenocarcinoma, and human HT-1080 fibrosarcoma cell lines. Based on the observed results, structure-activity relationships were discussed. Among the tested compounds, 7-hydroxy-6-methoxyflavanone (3) exhibited the most potent activity against B16-BL6 (IC(50), 6.66microM), LLC (IC(50), 9.29microM), A549 (IC(50), 8.63microM), and HT-1080 (IC(50), 7.94microM) cancer cell lines, and mucronulatol (26) against LLC (IC(50), 8.38microM) and A549 (IC(50), 9.9microM) cancer cell lines. These activity data were comparable to those of the clinically used anticancer drugs, 5-fluorouracil and doxorubicin, against the tested cell lines, suggesting that 3 and 26 are the good candidates for future anticancer drug development.

Topics: Animals; Brazil; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavanones; Flavonoids; HeLa Cells; Humans; Inhibitory Concentration 50; Mice; Molecular Structure; Neoplasms; Propolis; Stereoisomerism; Structure-Activity Relationship