Activation of the mitochondria-driven pathway of apoptosis in human PC-3 prostate cancer cells by a novel hydrophilic paclitaxel derivative, 7-xylosyl-10-deacetylpaclitaxel.
Paclitaxel, a natural product originally isolated from Taxus brevifolia, belongs to the most successful anticancer drugs. Nevertheless, its poor water solubility represents a considerable disadvantage in clinical use, and novel derivatives with improved pharmacological features are required. We isolated 7-xylosyl-10-deacetylpaclitaxel from Taxus chinensis, which reveals higher water solubility than paclitaxel. This compound induced mitotic cell cycle arrest and apoptosis as measured by flow cytometry, DNA laddering, and transmission electron microscopy. Pro-apoptotic Bax and Bad protein expression was up-regulated and anti-apoptotic Bcl-2 and Bcl-XL expression down-regulated, which lead to a disturbance of the mitochondrial membrane permeability and to the activation of caspase-9. In turn, caspase-9 activated downstream caspases-3 and -6, but not caspase-8. Bid was also activated by caspase-3. Reversely, treatment with a caspase-10-specific inhibitor could not protect PC-3 cells from 7-xylosyl-10-deacetyl-paclitaxel-triggered apoptosis. Moreover, 7-xylosyl-10-deacetylpaclitaxel had no effect on the expression of CD95 and NF-kappaB proteins, indicating that apoptosis was induced through the mitochondrial-dependent pathway in PC-3 cells.
Jiang
Shougang
S
Key Laboratory of Foresty Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin, P.R. China.
Zu
Yuangang
Y
Fu
Yuejie
Y
Zhang
Yu
Y
Efferth
Thomas
T
D017304:Annexin A5 / Q000032:analysis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053455:Caspase 10 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D020946:Taxus / Q000737:chemistry*; D051020:bcl-X Protein / Q000032:analysis; D019014:fas Receptor / Q000502:physiology
C531111:7-xylosyl-10-deacetylpaclitaxel; D017304:Annexin A5; D000972:Antineoplastic Agents, Phytogenic; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D016328:NF-kappa B; D051020:bcl-X Protein; D019014:fas Receptor; D053455:Caspase 10; D017239:Paclitaxel