Selective cytotoxicity of topoisomerase-directed protoberberines against glioblastoma cells

Sanders, Marilyn M.; Liu, Angela A.; Li, Tsai Kun; Wu, Hong; Desai, Shyamal D.; Mao, Yong; Rubin, Eric H.; LaVoie, Edmond J.; Makhey, Darshan; Liu, Leroy F.

doi:10.1016/s0006-2952(98)00243-3

Cited by 55 publications

(31 citation statements)

References 25 publications

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“…First, in contrast to the camptothecins, which are inactivated by lactone hydrolysis at physiological pH [19], the protoberberines are chemically stable. Second, the protoberberines induce a unique pattern of DNA cleavage sites relative to camptothecins [6,33,39], indicating that they may target the human genome differently and hence potentially exhibit a different spectrum of anticancer activity from the camptothecins [40,41]. However, the most severe factor which markedly limit the clinical use of the camptothecins is their toxicity profile; these compounds present a narrow therapeutic index, with a small difference between the dose required for an antitumour effect and that responsible for unacceptable toxicity; in addition, toxicity is observed earlier than the therapeutic effect [42].…”

Section: Resultsmentioning

confidence: 99%

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Kettmann

Kostálová

Höltje

2004

J Comput Aided Mol Des

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Using the X-ray crystal structure of the human topoisomerase I (top1) - DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the -1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.

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Section: Resultsmentioning

confidence: 99%

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Kettmann

Kostálová

Höltje

2004

J Comput Aided Mol Des

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“…Coralyne and its derivatives were shown to be inducers of topoisomerase I-DNA cleavable complexes, whereas the structurally similar benzophenanthridine alkaloid nitidine showed a dual poison activity for topoisomerases I and II (Pilch et al, 1997;Sanders et al, 1998;Makhey et al, 2000). In previous work from our laboratory, we have demonstrated that berberrubine has a potent activity as DNA topoisomerase II poison by stabilizing topoisomerase II-mediated cleavable complex in vitro .…”

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confidence: 86%

Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

Kang

Chung

2002

Mol Pharmacol

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Berberrubine, a protoberberine alkaloid that exhibits antitumor activity in animal models, has been identified as a specific poison of DNA topoisomerase II in vitro. To better understand the mechanisms of cellular response to berberrubine, human colorectal carcinoma cells (AMC5) were selected for resistance to berberrubine. The resulting cell line (AMC5/B1) was 5.3-fold resistant to berberrubine in the absence of MDR1 overexpression. The AMC5/B1 line was cross-resistant to topoisomerase II-targeted drugs but showed no cross-resistance to other antitumor drugs. The patterns of cross-resistance to various drugs led us to examine the cellular contents of topoisomerase II. Topoisomerase II activity was ϳ2.8-fold lower in AMC5/B1 cells compared with parental cells. The AMC5/B1 line contained ϳ5-fold decrease in topoisomerase II␣ protein level and ϳ2.5-fold decrease in topoisomerase II␣ mRNA level. A comparison of the degradation kinetics of topoisomerase II␣ mRNA demonstrated that there was no difference in mRNA stability between the two cell lines. Furthermore, the activity of topoisomerase II␣ promoter in AMC5/B1 cells was about 25% of that in AMC5 parental cells when transient transfection experiments were performed with the promoter-luciferase reporter gene. These results indicate that down-regulation of topoisomerase II␣ in AMC5/B1 cells occurs at the transcriptional level. Nucleotide sequencing of the topoisomerase II␣ promoter regions revealed no mutations in AMC5/B1 cells. In summary, resistance to berberrubine in AMC5 cells is associated with decreased level of catalytically active topoisomerase II␣, suggesting that topoisomerase II␣ is the cellular target of berberrubine in vivo.

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“…258 Berberine and several of its derivatives were shown to act as mammalian topoisomerase I and II inhibitors, although weakly 259 while coralyne and many of its derivatives were found to be strong inhibitors of DNA topoisomerase I. [260][261][262][263] The most significant aspect of the coralyne is its ability to inhibit DNA relaxation in a fashion significantly similar to the most potent antitumor alkaloid camptothecin that is known to exert this property. 263 Presumably, the most notable biological action of berberine and coralyne appears to the topoisomersae inhibition [259][260][261][262][263] that has direct relevance to their DNA intercalating property.…”

Section: B I O L O G I C a L P E R S P E C T I V E Smentioning

confidence: 99%

“…[260][261][262][263] The most significant aspect of the coralyne is its ability to inhibit DNA relaxation in a fashion significantly similar to the most potent antitumor alkaloid camptothecin that is known to exert this property. 263 Presumably, the most notable biological action of berberine and coralyne appears to the topoisomersae inhibition [259][260][261][262][263] that has direct relevance to their DNA intercalating property. More recent immunocytochemical studies in MCF-7 breast cancer cells showed that sanguinarine induces a striking disruption of normal cyclin and topoisomerase II trafficking, that inhibits the profileration of transformed cells.…”

Section: B I O L O G I C a L P E R S P E C T I V E Smentioning

confidence: 99%

Molecular aspects on the interaction of protoberberine, benzophenanthridine, and aristolochia group of alkaloids with nucleic acid structures and biological perspectives

Maiti

Kumar

2006

Medicinal Research Reviews

164

103

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Alkaloids occupy an important position in chemistry and pharmacology. Among the various alkaloids, berberine and coralyne of the protoberberine group, sanguinarine of the benzophenanthridine group, and aristololactam-beta-d-glucoside of the aristolochia group have potential to form molecular complexes with nucleic acid structures and have attracted recent attention for their prospective clinical and pharmacological utility. This review highlights (i) the physicochemical properties of these alkaloids under various environmental conditions, (ii) the structure and functional aspects of various forms of deoxyribonucleic acid (DNA) (B-form, Z-form, H(L)-form, protonated form, and triple helical form) and ribonucleic acid (RNA) (A-form, protonated form, and triple helical form), and (iii) the interaction of these alkaloids with various polymorphic DNA and RNA structures reported by several research groups employing various analytical techniques like absorbance, fluorescence, circular dichroism, and NMR spectroscopy; electrospray ionization mass spectrometry, thermal melting, viscosity, and DNase footprinting as well as molecular modeling and thermodynamic studies to provide detailed binding mechanism at the molecular level for structure-activity relationship. Nucleic acids binding properties of these alkaloids are interpreted in relation to their biological activity.

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Selective cytotoxicity of topoisomerase-directed protoberberines against glioblastoma cells

Cited by 55 publications

References 25 publications

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

Molecular aspects on the interaction of protoberberine, benzophenanthridine, and aristolochia group of alkaloids with nucleic acid structures and biological perspectives

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