Paclitaxel-induced apoptosis

Symmans W, Volm M, Shapiro R, et al. Paclitaxel-induced apoptosis and mitotic arrest assessed by serial needle aspiration implications for early prediction of breast cancer response to neoadjuvant treatment. Clin Cancer Res 2000 6 4610-4617. 

Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Baraldi PG, Borea PA (2007b) Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of Bad in glioblastoma cells. Mol Pharmacol 72(1) 162-172... 

Jazirehi AR, Bonavida B. 2004. Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin s lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis. Mol Cancer Ther 3 71-84. 

Ling Y, Zhong Y, Perez-Soler R. Disruption of cell adhesion and caspase-mediated proteolysis of beta- and gamma-catenins and APC protein in paclitaxel-induced apoptosis. Mol Pharmacol 2001 59 593-603. 

The involvement of many biochemical pathways and cytokines in paclitaxel-induced apoptosis has been extensively investigated. Among them, bcl-2, the well-known apoptosis inhibitor, was found to be phosphorylated in the presence of paclitaxel, with its inhibitory effect on apoptosis downregulated. One phosphorylation position is Ser-70, and the cells with Ser70 to Ala mutant showed lower reponse to paclitaxel-induced apoptosis. Deletion of the bcl-2 loop area comprising... 

Fan, W. Possible mechanisms of paclitaxel-induced apoptosis. Biochem. Pharmacol., 1999, 57 1215-1221. 

Carre, M., G. Carles, N. Andre, S. Douillard, J. Ciccolini, C. Briand and D. Braguer. Involvement of microtubules and mitochondria in the antagonism of arsenic trioxide on paclitaxel-induced apoptosis. Biochem. Pharmacol. 63 1831-1842, 2002. 

Parthenolide, isolated from Tanacetum parthenium and other species, is a sesquiterpene lactone widely investigated for its anti-inflammatory activity [168,169,170]. Recent in vitro studies have shown that this compound inhibits the NF-kB pathway. A study on the effect of parthenolide in endotoxic shock in rodents showed that treatment with this compound stopped nitrotyrosine formation, PARP synthetase expression, and apoptosis. It also reduced iNOS mRNA content in the tissues studied. All these effects are brought about by the compound s inhibition of NF-kB [171]. In addition, parthenolide mimicked the effects of IkBoc in that it inhibited both NF-kB DNA binding activity as well as Mn-SOD expression, while simultaneously increasing paclitaxel-induced apoptosis of breast cancer cells [90]. 

Low levels (0.1-1 pg/mL) of resveratrol have been reported to enhance cell proliferation, whereas higher amounts (10-100 pg/mL) cause apoptosis in a vari-ety of tumor and endothelial cells, including JB6 epidermal cells, human promyeloctye leukemia HL-60 cells, THP-1 human monocytic leukemia cells, U937 human promonocytic cells, various colon cancer cell lines, human mammary cancer cell lines, and human prostate cancer cells [121-131]. In somewhat of a contrast to these studies, a very recent report indicated that resveratrol reduced paclitaxel-induced apoptosis in a human neuroblastoma cell line (SH-SY5Y) by blocking paclitaxel-induced phosphorylation of JNKs, Raf-1, and BcT2 [132]. Of particular interest is a recent study in which it was shown to induce apoptosis in leukemic human lymphocytes but, under similar conditions, had no effect on the survival... 

Rigolio R, Miloso M, Nicolini G, Villa D, Scuteri A, Simone M, Tredici G (2005) Resveratrol interference with the cell cycle protects human neuroblastoma SH-SY5Y cell from paclitaxel-induced apoptosis. 

Fan W (1999) Possible Mechanisms of Paclitaxel-Induced Apoptosis. Biochem Pharmacol 57 1215... 

Cai J, Zheng T, Masood R, Smith DL, Hinton DR, Kim CN, Fang GF, Bhalla K, Gill PS (2000) Paclitaxel induces apoptosis in AIDS-related Kaposi s sarcoma cells. Sarcoma 4 37-45... 

Shiah SG, Chuang SE, Kuo ML. Involvement of Asp-Glu-Val-Asp-directed, caspase-mediated mitogen-activated protein kinase kinase 1 Cleavage, c-Jun N-terminal kinase activation, and subsequent Bcl-2 phosphorylation for paclitaxel-induced apoptosis in HL-60 cells. Mol Pharmacol 2001 59(2) 254—262. 

Of course other methods of radiation enhancement may take place with reoxygenation of hypoxic tumor cells that may be increased with the use of chemotherapies like paclitaxel or gemcitabine (41,42), improved drug access to the tumor cells after radiotherapy, or a lowering of the threshold for radiation-induced apoptosis as has been described with the use of gemcitabine (43). 

Wang TH, Wang HS, Soong YK. Paclitaxel-induced cell death where the cell cycle and apoptosis come together. Cancer 2000 88(ll) 2619-2628. 

It is widely assumed in the oncology therapeutic area that paclitaxel is cytotoxic to cancer cells and induces apoptosis, a rapid, programmed cell death associated with the activation of caspases (48) and mediated via the mitotic arrest of cells. 

However, this effect of paclitaxel was found to be dependent on the drug dose and cell type (49,50). A number of studies have demonstrated that paclitaxel has several biologic attributes that are critical to the cascade of events involved in preventing restenosis, Paclitaxel was shown to inhibit SMC proliferation over a broad concentration range (0.01 — 10,000 ng/mL) without causing cell death or apoptosis (49,51). A comparison of human coronary artery SMCs and HL60 leukemia cells showed that paclitaxel did not induce apoptosis in SMCs at concentrations as high as 10,000 ng/mL (Fig. 4) (49). 

Apoptosis is another important mechanism for cell poisoning, in addition to tubulin assembly promotion and microtubule stabilization for paclitaxel, especially at a high concentration (sub pM to pM level). It is also observed that in higher concentrations (5 to 50 pM), paclitaxel induced tumor necrosis through microtubules rather than apoptosis. " " Note that paclitaxel concentration in the clinic is lower than pM. 

Black cohosh 2. Caffeine 3. Evening primrose oil 4. Scutellaria baicalensis 5. Starflower (borage) 1. Docetaxel 2. Paclitaxel 3. Doxorubicin 4. Tamoxifen 5. Cisplatin 6. Vinorelbine t cytotoxic properties Unknown mechanism (black cohosh). Caffeine t cytotoxic effects of cisplatin wogonin present in Scutellaria enhances etoposide-induced apoptosis. Gamolenic acid found in evening primrose oil and borage potentiated the in vitro toxicity of paclitaxel and vinorelbine, attributed to an unsaturated fatty acid as modulators of tumour cell chemosensitivity Be aware and avoid concomitant use... 

Ahmed F, Pakunlu RI, Brannan A, Bates F, Minko T, Discher DE (2006) Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, inducing apoptosis in proportion to accumulated drug. J Contr Release 116 150-158... 

Apoptosis is an important process involved in the etiology, pathogenesis, and response to therapy of a variety of diseases. To develop a small molecule-based tracer for in vivo apoptosis imaging, a dansylhydrazone derivative (DFNSH) was synthesized in 93% yield in less than 30 minutes. The biological evaluation showed that DFNSH selectively binds to paclitaxel-induced apoptotic cancer cells and is localized within the cytoplasm of cells. [18F]-DFNSH was synthesized and isolated in 50-60% radiochemical yields. The straightforward preparation of fluorine-18 labeled DFNSH makes it a promising tracer for PET imaging of apoptosis. 

Paclitaxel belongs to the family of cytoskeletal drugs which target tubulin. Treatment leads to abnormality of the mitotic spindle assembly, chromosome segregation, and consequently defects of cell division. By stabilizing the microtubule polymer and preventing the disassembly of microtubules, paclitaxel arrests cell cycle in the GO/Gl and G2/M phases and induces apoptosis [134]. 

Balachandran, R., Terhaar, E., Welsh, M.J., Grant, S.G., and Day, B.W (1998) The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells preliminary comparisons to paclitaxel. Anti-Cancer Drugs, 9, 67-76. 

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