title: Intratumoral injection of taxol in vivo suppresses A549 tumor showing cytoplasmic vacuolization.
abstract: Based on our recent in vitro studies, this report was designed to explore the mechanism by which high concentration of taxol (70 µM) induced paraptosis-like cell death in human lung carcinoma (A549) cells, and to evaluate the therapeutic efficacy of taxol using A549 tumor-bearing mice in vivo. Exposure of cells to taxol induced time-dependent cytotoxicity and cytoplasmic vacuolization without the involvement of Bax, Bak, Mcl-1, Bcl-XL, and caspase-3. Although taxol treatment induced activating transcription factor 6 (ATF6) cleavage indicative of endoplasmic reticulum (ER) stress, silencing ATF6 by shATF6 did not prevent taxol-induced both cytotoxcity and cytoplasmic vacuolization, suggesting that taxol-induced cytoplasmic vacuolization and cell death were not due to ER stress. Moreover, taxol-treated cells did not show DNA fragmentation and loss of mitochondrial membrane potential, the typical characteristics of apoptosis. In addition, taxol-induced cytoplasmic vacuolization did not show the cellular lysis, the characteristics of oncosis, and positive of β-galactosidase, the characteristic of senescence, indicating that taxol induced paraptosis-like cell death is neither oncosis nor senescence. Moreover, our in vivo data showed that intratumoral injection of taxol (50 mg/kg) in A549 tumor xenograft mice on day 1 and day 19 potently suppressed tumor growth showing significant ER vacuolization without toxicity. In conclusion, high concentration of taxol exhibits a significant anticancer activity by inducing paraptosis-like cell death in vitro and in vivo, without significant toxicity, suggesting a promising therapeutic strategy for apoptosis-resistance cancer by inducing ER vacuolization.
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Wang
authors.forename: Tongsheng
authors.initials: T
authors.lastname: Chen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000187:drug effects*; D017931:DNA Primers; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D046529:Microscopy, Electron, Transmission; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014617:Vacuoles / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D017239:Paclitaxel