Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons

Makhey, Darshan; Gatto, Barbara; Yu, Chiang; Liu, Angela; Liu, Leroy F.; LaVoie, Edmond J.

doi:10.1016/0968-0896(96)00054-5

Cited by 97 publications

(65 citation statements)

References 27 publications

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“…Protoberberine alkaloids are a new class of organic cations that exhibit topoisomerase poison activity Makhey et al, 1996;Li et al, 2000). 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).…”

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confidence: 99%

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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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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“…Some studies suggest that berberine may either directly bind duplex DNA by intercalation (27)(28)(29)(30) or inflict DNA damage indirectly by its interaction with topoisomerases I and II (28,(31)(32)(33). Other investigators also showed that berberine at 150 mg/ml was able to induce the rate of sister chromatid exchanges, which reflects homologous recombination repair, by several fold (34).…”

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confidence: 99%

Involvement of reactive oxygen species and caspase-dependent pathway in berberine-induced cell cycle arrest and apoptosis in C6 rat glioma cells

et al. 2009

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Abstract. The cytotoxicity of berberine on C6 rat glioma cells indicated that berberine induced morphological changes and caused cell death through G2/M arrest and apoptosis. While undergoing apoptosis, there was a remarkable accumulation of G2/M cells with the upregulatoin of Wee1 but it also inhibited cyclin B, CDK1 and Cdc25c that led to G2/M arrest. Along with cytotoxicity in C6 cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3 and -8 and DNA fragmentation were induced. Berberine increased the levels of GADD153 and GRP 78 in C6 cells based on the examination of Western blotting and this is a major hallmark of endoplasmic reticulum (ER) stress. We also found that berberine promoted the production of reactive oxygen species and Ca 2+ in C6 cells. Western blotting assay also showed that berberine inhibited the levels of anti-apoptotic protein Bcl-2 but increased the levels of pro-apoptotic protein Bax before leading to a decrease in the levels of mitochondrial membrane potential (Δae m ) followed by cytochrome c release that caused the activations of capase-9 and -3 for apoptotic occurrence. The caspase-8, -9 and -3 were activated by berberine in C6 cells based on the substrate solution (PhiPhiLux-G 1 D 1 , CaspaLux 8-L 1 D 2 , CaspaLux 9-M 1 D 2 for caspase-3, -8 and -9, respectively) and analyzed by flow cytometer and each inhibitor of caspase-8, -9 and -3 led to increase the percentage of viable C6 cells after exposure to berberine. This finding was also confirmed by Western blot assay which showed that berberine promoted the active form of caspase-8, -9 and -3. These results demonstrate that the cytotoxicity of berberine in C6 rat glioma cells is attributable to apoptosis mainly through induced G2/M-arrested cells, in an ER-dependent manner, via a mitochondria-dependent caspase pathway regulated by Bax and Bcl-2.

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“…TCE contains berberine that has been found to be a topoisomerase II inhibitor. 47) Other topoisomerase II inhibitors like etoposide and teniposide have been found to exert antineoplastic activity. 48) CONCLUSIONS From our study it is clear that the TCE is a composite mixture of various alkaloids including berberine.…”

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confidence: 99%

Evaluation of the Antineoplastic Activity of Guduchi (Tinospora cordifolia) in Ehrlich Ascites Carcinoma Bearing Mice

Jagetia

Rao

2006

Biological & Pharmaceutical Bulletin

141

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Chemotherapy is a major treatment modality for cancer and some of the plants like Catharanthus roseus, Podophyllum peltatum, P. emodii, Taxus brevifolia, Ochrosia elliptica and Campototheca acuminata, have provided active principles which are in clinical use for controlling advanced stages of malignancies.1) However, most of these chemotherapeutic agents exhibit severe normal toxicity, resulting in undesirable side effects. Moreover, many of the active molecules sold for the treatment of cancer, are highly expensive, mutagenic, carcinogenic and teratogenic. Hence, there is a need to find alternative drugs, which are highly effective at non-toxic doses, inexpensive and accessible to common man. A need is therefore felt to search newer remedies, which are cheaper economically and do not have severe side effects of the pure compounds.Medicines derived from plants have played a pivotal role in health care of ancient and modern cultures. Ayurveda, the Indian system of medicine mainly uses plant based drugs or formulations to treat various ailments including cancer. Recent surveys suggest that one in three Americans uses dietary supplements daily and the rate of usage is much higher in cancer patients, which may be up to 50% of patients treated in cancer centers. 2)Tinospora cordifolia (WILLD.) MIERS ex HOOK. F. & THOMS is a large, glabrous, deciduous climbing shrub belonging to the family Menispermaceae.3,4) It is distributed throughout tropical Indian subcontinent and China, ascending to an altitude of 300 m. The plant is commonly known as Guduchi, Giloy or Amritha, which are Hindu mythological terms that refer to the heavenly elixir that have saved celestial beings from old age and kept them eternally young. Guduchi is widely used in veterinary folk medicine and Ayurvedic system of medicine for its general tonic, antiperiodic, anti-spasmodic, anti-inflammatory, antiarthritic, anti-allergic and antidiabetic properties.5-7) The whole plant is used in Ayurvedic "Rasayanas" to improve the immune system and the body resistance against infections and root is known for its antistress, anti-leprotic and anti-malarial activities. 7,8) Guduchi has been reported to be active against throat cancer in man and it has been reported to be non-toxic in acute toxicity studies in vivo, with almost no side effects. [9][10][11] A variety of constituents have been isolated from T. cordifolia and their structures elucidated. They belong to different classes such as alkaloids, diterpenoid lactones, glycosides, steroids, sesquiterpenoid, phenolics, aliphatic compounds and polysaccharides. Leaves of T. cordifolia are rich in protein (11.2%) and are fairly rich in calcium and phosphorus.7,12) Alkaloids like berberine, palmatine, tembetarine and magnoflorine have been isolated from the stem of T. cordifolia. The roots of T. cordifolia are also reported to contain other alkaloids like choline, tinosporin, isocolumbin, palmatine, tetrahydropalmatine and magnoflorine.13-18) Our preliminary studies on the stem extracts of T. cordifolia have shown...

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Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons

Cited by 97 publications

References 27 publications

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

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

Involvement of reactive oxygen species and caspase-dependent pathway in berberine-induced cell cycle arrest and apoptosis in C6 rat glioma cells

Evaluation of the Antineoplastic Activity of Guduchi (Tinospora cordifolia) in Ehrlich Ascites Carcinoma Bearing Mice

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