Cytotoxicity and cell cycle effects of the plant alkaloids cryptolepine and neocryptolepine: relation to drug-induced apoptosis

Dassonneville, Laurent; Lansiaux, Amélie; Wattelet, Aurélie; Wattez, Nicole; Mahieu, Christine; Miert, Sabine Van; Pieters, Luc; Bailly, Christian

doi:10.1016/s0014-2999(00)00805-0

Cited by 145 publications

(92 citation statements)

References 41 publications

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“…The parallelstranded psD duplex results from the association of two AT strands. The 24CTG mimics eight repeats of the trinucleotide unit (CTG) 8 . ds26 is a duplex formed with a self-complementary oligonucleotide.…”

Section: Dialysis Experimentsmentioning

confidence: 99%

“…It also intercalates into GC-rich sequences and interferes with the catalytic activity of human topoisomerase II, although less efficiently than cryptolepine [7]. Cryptolepine and neocryptolepine have cytotoxic effects and induce apoptosis in HL60 leukaemia cells [8]. Recently, the structure of a cryptolepine-DNA complex was elucidated by X-ray crystallography.…”

Section: Introductionmentioning

confidence: 99%

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Interactions of cryptolepine and neocryptolepine with unusual DNA structures

et al. 2003

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1 These authors contributed equally to this work. AbstractCryptolepine, the main alkaloid present in the roots of Cryptolepis sanguinolenta, presents a large spectrum of biological properties. It has been reported to behave like a DNA intercalator with a preference for GC-rich sequences. In this study, dialysis competition assay and mass spectrometry experiments were used to determine the affinity of cryptolepine and neocryptolepine for DNA structures among duplexes, triplexes, quadruplexes and single strands. Our data confirm that cryptolepine and neocryptolepine prefer GC over AT-rich duplex sequences, but also recognize triplex and quadruplex structures. These compounds are weak telomerase inhibitors and exhibit a significant preference for triplexes over quadruplexes or duplexes.

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Section: Dialysis Experimentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

et al. 2003

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“…CLP was first isolated from Cryptolepis sanguinolenta (24) that is native to Central and West Anti-malaria activity of CLP was reported previously (26). In addition, it has been reported that CLP can suppress the growth of cancer cells in vitro by inhibiting cell cycle progression and causing apoptosis in human HL-60 leukemia (27) and B16 melanoma cells (28,29). However, the molecular mechanisms for the effect in the growth arrest of cancer cells by CLP have not yet been studied.…”

Section: Introductionmentioning

confidence: 99%

The plant alkaloid cryptolepine induces p21WAF1/CIP1 and cell cycle arrest in a human osteosarcoma cell line

Matsui

Sowa²,

Murata³

et al. 2007

Int J Oncol

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Abstract. We previously established a bioassay method to screen for compounds that activate the promoter activity of p21 WAF1/CIP1 , a potent inhibitor of cyclin-dependent kinases, in a p53-independent manner. As an activator of p21 WAF1/CIP1promoter activity, we isolated cryptolepine (CLP: 5-methyl indolo (2,3b)-quiniine), an indoloquinoline alkaloid, from the traditional Ayurvedic medicinal plant Sida cordifolia. We show here that CLP induces the expression of p21 WAF1/CIP1with growth arrest in p53-mutated human osteosarcoma MG63 cells. Four micromolar of CLP completely inhibited the growth of MG63 cells and caused G 2 /M-phase arrest. CLP up-regulated the expression of p21 WAF1/CIP1 at both mRNA and protein levels in a dose-dependent manner. Using several mutant p21 WAF1/CIP1 promoter constructs, we found that the CLP-responsive element is an Sp1 site at -82 relative to the transcription start site of the p21 WAF1/CIP1 promoter. These findings suggest that CLP arrests the growth of MG63 cells by activating the p21 WAF1/CIP1 promoter through the specific Sp1 site in a p53-independent manner. In addition, CLPmediated cell cycle arrest was reduced by the knockout of the p21 WAF1/CIP1 gene in human colon cancer HCT116 cells, suggesting that the cell cycle arrest by CLP was at least partially mediated through the induction of p21expression. Although we need further study of chemotherapeutic effect in vivo, these results raise the possibility that CLP might be a suitable chemotherapeutic agent for treatment of osteosarcoma. IntroductionOsteosarcoma is the most common form of primary malignant bone tumor that mainly occurs in juvenile patients. Although the development of effective adjuvant regimen of chemotherapy has substantially improved the prognosis of patients (1-4), >20% of patients still die as a result of tumor metastasis (5-10). One of the most serious causes of therapeutic failure is the resistance of the tumor cells to chemotherapeutic agents (11,12). To overcome the drug resistance, new anti-tumor agents or chemicals and new anti-tumor therapeutic approaches need to be developed. p21 WAF1/CIP1 is a member of the cyclin-dependent kinase inhibitors and induces G 1 -and G 2 /M-phase cell cycle arrest (13-16). p21 WAF1/CIP1 induces differentiation of both normal and transformed cells and suppresses the growth of malignant cells, in vitro and in vivo (17,18 WAF1/CIP1 is an attractive molecular target to suppress cell growth even in p53-mutated cancer cells and p21 WAF1/CIP1 -inducing agents by a p53-independent pathway might be effective for chemotherapy of osteosarcoma with poor prognosis.Recently, we established a bioassay method using p53-negative human osteosarcoma MG63 cells to screen for compounds that activate the p21 WAF1/CIP1 promoter activity in a p53-independent manner (23). As an activator of p21 WAF1/CIP1 promoter activity, we isolated cryptolepine (CLP: 5-methyl indolo (2,3b)-quiniine), an indoloquinoline alkaloid, from the traditional Ayurvedic medicinal plant Sida cordifolia. CLP was first is...

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“…Pelo fato de muitos medicamentos utilizados no tratamento para câncer apresentarem estrutura semelhante ao de um alcalóide, atualmente estão isolando alcalóides de herbáceos nunca antes estudados para verificar os seus possíveis efeitos sobre a doença . Embora a maioria dos estudos com alcalóides tenha como característica química comum grupamentos fenólicos (MCNULTY et al, 2007;GRIFFIN et al, 2007) (BAO et al, 2004;DASSONNEVILLE et. al., 2000).…”

Section: Discussionunclassified

Sinalização celular para apoptose em linhagem celular de adenocarcinoma (MCF-7) e carcinoma ductal invasivo de mama (ZR 7531) tratados com alcalódes isolados de Pterogyne nitens

Duarte¹

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Sinalização celular para apoptose em linhagem celular de adenocarcinoma (MCF-7) e carcinoma ductal invasivo de mama (ZR 7531) tratadas com alcalóides isolados de Pterogyne nitens ARARAQUARA -SPÀ Camila Araki uma pessoa maravilhosa e competente, que esteve sempre presente e auxiliou-me em todos os momentos.Aos membros da banca examinadora, pela disponibilidade e competência na avaliação deste trabalho.À Regina, pela amizade, carinho e atenção, sempre me apoiando.Às queridas amigas Ana Paula, Débora, Rita Karina, que sempre estiveram ao meu lado em todos os momentos, muito obrigadas pela amizade, carinho, incentivo, apoio e por toda ajuda. À todos do laboratório de Citologia e Biologia Celular, estagiários e pós-graduandos, que de uma forma ou de outra contribuíram para a realização deste trabalho Aline, Angélica, Camila Olivato, Claudete, Daniele, Felipe, Heloísa, Isabel, Jamile, Juliana, Mauro, Maura, Rochane.À Elaine e a Tarsia pela imprescendível colaboração durante a realizção deste trabalho, pelo apoio e estímulo, meus afetivos agradecimentos.Ao Ederlan e Delfina pelo auxílio nas etapas finais deste trabalho.À Maria Isabel pelo apoio técnico e competência com que trabalha pelo nosso laboratório, e principalmente, pela amizade, carinho, preocupação, incentivo e pela certeza de sempre poder contar com sua sinceridade.Ao Max, com quem compartilhei momentos de angústias, por sempre me ajudar a ver o lado positivo de todos acontecimentos e com isso ter proporcionado importantes momentos de descontração.Às meninas da pós-graduação Angela, Cláudia, Laura e Sônia pela dedicação e competência com que trabalham pelo nosso curso, pelo acolhimento que nos proporciona e, principalmente, pela amizade e carinho. mama. Para avaliação da apoptose foi observado um intense efeito concentração-resposta em apoptose tardia/necrose e discreto sinal para apoptose precoce em todas concentrações (p<0,01). No ensaio Hoechst/iodeto, observou diferença significante entre os estágios de apoptose precoce e tardia de ambas linhagens. A pteroginina no período t0 e t24, e pteroginidina no período t0 demonstraram possuir intenso efeito concentração resposta para apoptose tardia e discreto efeito para apoptose precoce em todas as concentrações (p<0,01). Entretanto a linhagem MCF-7 tratada com pteroginidina (t24) demonstrou intenso efeito concentração-resposta para necrose (p<0,01). Atividade de caspase 3/7 foi significativamente maior na concentração de 1,125 mM com pteroginina por t0 (p<0,05). Conclusão: Podemos concluir que PGN e PGD possuem efeito anticarcinogênico contra células de câncer de mama in vitro, induzindo a morte celular programada.Palavras-chave: linhagem cancer de mama, atividade citotoxica, alcalóides, apoptose, necrose, citometria de fluxo. ABSTRACTIntroduction: Breast cancer is a major cause of morbidity and mortality among

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Cytotoxicity and cell cycle effects of the plant alkaloids cryptolepine and neocryptolepine: relation to drug-induced apoptosis

Cited by 145 publications

References 41 publications

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

The plant alkaloid cryptolepine induces p21WAF1/CIP1 and cell cycle arrest in a human osteosarcoma cell line

Sinalização celular para apoptose em linhagem celular de adenocarcinoma (MCF-7) e carcinoma ductal invasivo de mama (ZR 7531) tratados com alcalódes isolados de Pterogyne nitens

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