Inhibition of thymidylate synthase and cell growth by the phenanthroindolizidine alkaloids pergularinine and tylophorinidine

Rao, K. N.; Bhattacharya, R.K.; Venkatachalam, S. R.

doi:10.1016/s0009-2797(97)00065-3

Cited by 35 publications

(19 citation statements)

References 28 publications

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“…However, more evidence may be needed to bolster the relationship between antitumor activity and cytotoxicity and the inhibitions in the activation of cAMP response element, AP1, and NF-B by these tylophorine analogs. In addition, another two phenanthroindolizidine alkaloids, pergularine and tylophorinidine, were found to inhibit the activity of dihydrofolate reductase and thymidylate synthase, which may account for their underlying mechanisms for anticancer activity (Rao et al, 1997;Rao and Venkatachalam, 2000).…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Mechanisms of Phenanthroindolizidine Alkaloids

Yang¹,

Chen²,

Wu³

et al. 2005

Mol Pharmacol

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The molecular mechanisms for the anti-inflammatory activity of phenanthroindolizidine alkaloids were examined in an in vitro system mimicking acute inflammation by studying the suppression of lipopolysaccharide (LPS)/interferon-␥ (IFN␥)-induced nitric oxide production in RAW264.7 cells. Two of the phenanthroindolizidine alkaloids, NSTP0G01 (tylophorine) and NSTP0G07 (ficuseptine-A), exhibited potent suppression of nitric oxide production and did not show significant cytotoxicity to the LPS/IFN␥-stimulated RAW264.7 cells, in contrast to their respective cytotoxic effects on cancer cells. Tylophorine was studied further to investigate the responsible mechanisms. It was found to inhibit the induced protein levels of tumor necrosis factor-␣, inducible nitric-oxide synthase (iNOS), and cyclooxygenase (COX)-II. It also inhibited the activation of murine iNOS and COX-II promoter activity. However, of the two common responsive elements of iNOS and COX-II promoters, nuclear factor-B (NF-B) and adaptor protein (AP)1, only AP1 activation was inhibited by tylophorine in the LPS/IFN␥-stimulated RAW264.7 cells. Further studies showed that the tylophorine enhanced the phosphorylation of Akt and thus decreased the expression and phosphorylation levels of c-Jun protein, thereby causing the subsequent inhibition of AP1 activity. Furthermore, the tylophorine was able to block mitogen-activated protein/extracellular signal-regulated kinase kinase 1 activity and its downstream signaling activation of NF-B and AP1. Thus, NSTP0G01 exerts its anti-inflammatory effects by inhibiting expression of the proinflammatory factors and related signaling pathways.Phenanthroindolizidine alkaloids are a small group of compounds well known for their profound cytotoxic activity (Pettit et al., 1984;Abe et al., 1998;Staerk et al., 2000Staerk et al., , 2002 and thus have been exploited as potential therapeutic leads for anticancer agents (Staerk et al., 2002). These alkaloids were also shown to have anti-inflammatory, antiasthmatic, and antianaphylactic properties with consequences of altered immunological status in vivo (Gopalakrishnan et al., 1979(Gopalakrishnan et al., , 1980Raina and Raina, 1980;Ganguly and Sainis, 2001;Staerk et al., 2002). Although adenyl cyclase was stimulated in asthmatic patients' peripheral leukocytes treated with tylophorine (Raina and Raina, 1980), the molecular mechanisms of actions of these phenanthroindolizidine alkaloids for aforementioned functions are not clear as yet. Moreover, the analysis and knowledge of the structure-activity relationships of the phenanthroindolizidine alkaloids with their biological function are also scarce.Inflammation is a central feature of many pathological conditions and is mediated by a variety of soluble factors and cellular signaling events. For example, NF-B-dependent gene expression plays an important role in inflammatory responses and increases the expression of genes encoding cytokines and receptors involved in proinflammatory enzymes such as iNOS and COX-II (Giuliani et al....

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Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Mechanisms of Phenanthroindolizidine Alkaloids

Yang¹,

Chen²,

Wu³

et al. 2005

Mol Pharmacol

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“…Tylophorine and some analogs were synthesized as early as 1960 (38), and their inhibition of protein and nucleic acid synthesis has been documented (2,4). A comprehensive evaluation of their antitumor potential has not been reported, and mechanisms of growth inhibition are largely unknown.…”

Section: -3500 and Dcb-3503 Induce S-phase Accumulation In Kb Cells Bmentioning

confidence: 99%

“…These compounds, commonly referred to as tylophora alkaloids, because of their reported antitumor activity (1)(2)(3)(4)(5)(6)(7)(8), have been the targets of synthesis, modification, and antitumor evaluation in our laboratories. Evaluation of (ϩ)-(S)-tylophorine [DCB-3500 (NSC-717335)] and its analog DCB-3503 (NSC-716802) in the antitumor screen at the National Cancer Institute showed a fairly uniform and potent growth-inhibitory activity (GI 50 , ϳ10 Ϫ8 M) in all 60 cell lines, with notable selectivity toward several refractory cell lines, including melanoma and lung tumor cell lines based on LC 50 values (concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared with that at the beginning).…”

Section: Introductionmentioning

confidence: 99%

Novel Mode of Action of Tylophorine Analogs as Antitumor Compounds

et al. 2004

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“…Wight and Arn (Asclepiadaceae)] inhibited the growth of Lactobacillus leichmanni cells by binding to thymidylate synthetase. 24 Anthraquinone natural products like rubidianin, isolated from the alcoholic extract of Rubia cordifolia, demonstrated significant antioxidant activity in a dosedependent manner. It prevented lipid peroxidation induced by ferrous sulphate and t-butylhydroperoxide.…”

Section: Antioxidants and Cancermentioning

confidence: 99%