securinine and 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

Cancer with low survival rates is the second main cause of death among all diseases in the world and consequently, effective antineoplastic agents are urgently needed. Allosecurinine is a plant-derived indolicidine securinega alkaloid shown bioactivity. The object of this study is to investigate synthetic allosecurinine derivatives with considerable anticancer capacity against nine human cancer cell lines as well as mechanism of action. We synthesized twenty-three novel allosecurinine derivatives and evaluated their antitumor activity against nine cancer cell lines for 72 h by MTT and CCK8 assays. FCM was applied to analyze the apoptosis, mitochondrial membrane potential, DNA content, ROS production, CD11b expression. Western blot was selected to analyze the protein expression. Structure-activity relationships were established and potential anticancer lead BA-3 which induced differentiation of leukemia cells towards granulocytosis at low concentration and apoptosis at high concentration was identified. Mechanism studies showed that mitochondrial pathway mediated apoptosis within cancer cells with cell cycle blocking was induced by BA-3. In addition, western blot assays revealed that BA-3 induced expression of the proapoptotic factor Bax, p21 and reduced the levels of antiapoptotic protein such as Bcl-2, XIAP, YAP1, PARP, STAT3, p-STAT3, and c-Myc. Collectively, BA-3 was a lead compound for oncotherapy at least in part, through the STAT3 pathway. These results were an important step in further studies on allosecurinine-based antitumor agent development.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Azepines; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neoplasms

Analysis of the anticancer and antimitotic activity of the plant derived alkaloid securinine along with its effect on the organization of cellular microtubules as well as its binding with purified goat brain tubulin in-vitro.. The cytotoxicity of securinine on different cell lines was conducted using SRB assay. The effect of securinine on the cellular microtubules was analyzed using immunofluorescence microscopy. The binding of securinine on purified goat brain tubulin was evaluated using fluorescent spectroscopy.. Securinine effectively prevented the proliferation of cervical, breast and lung cancer cells with an IC. Considering the strong anticancer and anti-metastatic property and low toxicity in non-malignant cell lines, we suggest that securinine can be used as a chemotherapeutic drug either alone or in combination with other known anticancer molecules.

Topics: A549 Cells; Antineoplastic Agents; Azepines; Dose-Response Relationship, Drug; HEK293 Cells; HeLa Cells; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; MCF-7 Cells; Microtubules; Mitosis; Neoplasms; Piperidines; Tubulin

Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicine Securinega suffruticosa, has been established clinical success in treatment of neurological disorders. Recently, increasing evidence demonstrates that SCR has potential cytotoxicity to various types of tumor cells, which enables this old central nervous system drug as a potential cancer therapeutic agent. However, the mechanism underlying the anticancer activity of SCR is not well defined. We reported here that SCR inhibits both the purified TrxR and the enzyme in intact cells. SCR elicits accumulation of reactive oxygen species (ROS), elevation of oxidized glutathione and Trx, disturbs redox homeostasis, and eventually leads to oxidative stress-mediated HeLa cell apoptosis. Importantly, pharmacological inhibition or knockdown of TrxR sensitizes the cells to SCR treatment, underpinning the physiological significance of targeting TrxR by SCR. Our discovery discloses a novel mechanism underlying the anticancer activity of SCR and provides basic data for further development of SCR as a cancer chemotherapeutic drug.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Azepines; Cell Line, Tumor; Enzyme Inhibitors; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neoplasms; Oxidation-Reduction; Oxidative Stress; Piperidines; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase

A series of new securinine analogues was prepared by Heck reaction from readily accessible securinine and commercially available iodoarenes. The in vitro cytotoxicity of the prepared compounds was assayed against a panel of four cancer cell lines: A375, A549, HCT-116 and HL-60 showing promising growth inhibition with excellent IC50 values in the nanomolar range. The plasmatic stability of the most potent analogue was also investigated demonstrating that they might serve as valuable leads for the development of anticancer drugs.

Topics: Antineoplastic Agents; Apoptosis; Azepines; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neoplasms; Piperidines