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Dual inhibition of topoisomerase II and microtubule of podophyllotoxin derivative 5p overcomes cancer multidrug resistance.
Lv, Xing; Cheng, Wei-Hua; Li, Xiao-Xue; Shang, Hai; Zhang, Jun-Yi; Hong, Han-Yu; Zheng, Yi-Jia; Dong, Yan-Qun; Gong, Jian-Hua; Zheng, Yan-Bo; Zou, Zhong-Mei.
Afiliación
  • Lv X; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili, 100050, Beijing, China.
  • Cheng WH; HTA Co., Ltd., CAEA Center of Excellence on Nuclear Technology Applications for Engineering and Industrialization of Radiopharmaceuticals, CNNC Engineering Research Center of Radiopharmaceuticals, 102413, Beijing, China.
  • Li XX; The State Key Laboratory of Basis and New Drug Development of Natural and Nuclear Drugs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, 100193, Beijing, China.
  • Shang H; The State Key Laboratory of Basis and New Drug Development of Natural and Nuclear Drugs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, 100193, Beijing, China.
  • Zhang JY; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili, 100050, Beijing, China.
  • Hong HY; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili, 100050, Beijing, China.
  • Zheng YJ; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili, 100050, Beijing, China.
  • Dong YQ; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili, 100050, Beijing, China.
  • Gong JH; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili, 100050, Beijing, China. Electronic address: ann_gong@imb.pumc.edu.cn.
  • Zheng YB; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan Xili, 100050, Beijing, China. Electronic address: zhengyb@imb.pumc.edu.cn.
  • Zou ZM; The State Key Laboratory of Basis and New Drug Development of Natural and Nuclear Drugs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, 100193, Beijing, China. Electronic address: zmzou@implad.ac.cn.
Eur J Pharmacol ; 983: 176968, 2024 Nov 15.
Article en En | MEDLINE | ID: mdl-39233039
ABSTRACT
Compound 5p is a 4ß-N-substituted podophyllotoxin derivative, which exhibited potent activity toward drug-resistant K562/A02 cells and decreased MDR-1 mRNA expression. Here, we further investigated its detail mechanism and tested its antitumor activity. 5p exerted catalytic inhibition of topoisomerase IIα, and didn't show the inhibitor of topoisomerase I. 5p exhibited the inhibitory effect on microtubule polymerization. 5p showed potent anti-proliferation against breast cancer, oral squamous carcinoma, and their drug-resistant cell lines, with resistance index of 0.61 and 0.86, respectively. 5p downregulated the expression levels of P-gp in KBV200 cells and BCRP in MCF7/ADR cells in dose-dependent manner. Moreover, 5p induced KB and KBV200 cells arrest at G2/M phase by up-regulating the expression of γ-H2AX, p-Histone H3 and cyclin B1. 5p induced apoptosis and pyroptosis by increased the expression levels of cleaved-PARP, cleaved-caspase3, N-GSDME as well as LDH release in KB and KBV200 cells. In addition, 5p efficiently impaired tumor growth in KB and KBV200 xenograft mice. Conclusively, this work elucidated the dual inhibitor of topoisomerase II and microtubule of 5p and its mechanism of overcoming the multidrug resistance, indicating that 5p exerts the antitumor potentiality.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Podofilotoxina / ADN-Topoisomerasas de Tipo II / Resistencia a Múltiples Medicamentos / Resistencia a Antineoplásicos / Inhibidores de Topoisomerasa II / Microtúbulos Límite: Animals / Female / Humans Idioma: En Revista: Eur J Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Podofilotoxina / ADN-Topoisomerasas de Tipo II / Resistencia a Múltiples Medicamentos / Resistencia a Antineoplásicos / Inhibidores de Topoisomerasa II / Microtúbulos Límite: Animals / Female / Humans Idioma: En Revista: Eur J Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos