Bcl-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells.

Gazitt, Yair; Rothenberg, M.L.; Hilsenbeck, Susan G.; Fey, Vidal; Thomas, Christoforos; Montegomrey, W

doi:10.3892/ijo.13.4.839

Cited by 46 publications

(60 citation statements)

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“…Furthermore, consistent with published literature (17,40,41), we have also shown here that BCL-2 mediates ARTN acquired radio-and chemo-resistance and the CSC-like characteristics in ER-MC cells. ARTN expression was significantly and positively correlated with BCL-2 expression in a cohort of ER-MC.…”

Section: Discussionsupporting

confidence: 80%

Artemin Stimulates Radio- and Chemo-resistance by Promoting TWIST1-BCL-2-dependent Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

Banerjee

Qian

et al. 2012

Journal of Biological Chemistry

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Background:Artemin is an oncogenic and metastatic factor in mammary carcinoma. Results: Artemin promotes radio-and chemo-resistance by enhancing TWIST1-BCL-2-dependent cancer stem cell like behavior in mammary carcinoma cells. Conclusion: Artemin functions as a cancer stem cell (CSC) factor in mammary carcinoma cells. Significance: Functional inhibition of ARTN may be useful to inhibit CSC activity in mammary carcinoma.

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Section: Discussionsupporting

confidence: 80%

Artemin Stimulates Radio- and Chemo-resistance by Promoting TWIST1-BCL-2-dependent Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

Banerjee

Qian

et al. 2012

Journal of Biological Chemistry

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“…[35][36][37] The extent of gemcitabine-induced apoptosis, however, has been reported to be independent of the levels of Bcl-2 expression. 38 Our results show strongly reduced Bcl-2 and Bcl-X/L protein levels in the wt-p53 cells after gemcitabine treatment whereas in mut-p53 cells exposed to gemcitabine Bcl-2 levels did not vary and Bcl-X/L levels were increased. Bax protein increased in both lines after exposure to gemcitabine, suggesting a p53-independent induction mechanism.…”

Section: Discussionmentioning

confidence: 43%

Expression of a non‐functional p53 affects the sensitivity of cancer cells to gemcitabine

Galmarini

Clarke

Falette

et al. 2001

Intl Journal of Cancer

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Gemcitabine is a relatively new agent with promising activity in solid tumors. Few data are available regarding mechanisms of resistance to gemcitabine downstream from the drug-target interaction. The present study was performed to gain insight into the role of p53 status on the cytotoxicity of gemcitabine on cancer cells. Drug sensitivity, drug metabolism, cell kinetics and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the wildtype p53 (wt-p53) containing MN-1 cell line and, the MDD2 line containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to gemcitabine cytotoxicity than the MN-1 cell line. The resistant phenotype could not be attributed to a defective gemcitabine activation/degradation pathway or altered levels of expression of intracellular targets. Although both cell lines exhibited p53 accumulation, MN-1 but not MDD2 cells, displayed p21 WAF1 induction after exposure to gemcitabine. Gemcitabine induced an S-phase arrest in both cell lines. A more pronounced block in G1 phase, however, was observed in MN1 cells. Exposure to gemcitabine induced a higher degree of apoptosis in MN-1 than in MDD2 cells. This corresponded with suppression of Bcl-2 and Bcl-X/L expression in wt-p53 cells exposed to gemcitabine whereas Bcl-2 levels remained stable and Bcl-X/L levels increased in mut-p53 cells exposed to gemcitabine. We conclude that the p53 status of cancer cells influences their sensitivity to gemcitabine cytotoxicity. Our evidence suggests that loss of p53 function leads to loss of cell cycle control and alterations in the apoptotic cascade, conferring resistance to gemcitabine in cancer cell lines displaying a mut-p53. © 2002 Wiley-Liss, Inc. Key words: protein p53; drug resistance; gemcitabine; antimetabolites; cell death; apoptosisGemcitabine (difluorodeoxycytidine; dFdC) is an agent with promising activity in solid tumors. [1][2][3] This compound is a deoxycytidine analog with two fluorine substitutes for the two hydrogen atoms in the 2Ј position of the deoxyribose sugar. Gemcitabine activity is dependent upon the formation of a triphosphorylated metabolite that is subsequently incorporated into DNA.Gemcitabine enters the cell via a nucleoside transport system 4,5 and is phosphorylated into dFd-CMP by deoxycytidine kinase (dCK). 6 It is then subsequently phosphorylated by monophosphoand diphospho-pyrimidine kinases to the active 5Ј-diphosphate (dFd-CDP) and triphosphate (dFd-CTP) derivatives. 7 Inactivation of gemcitabine can occur by deamination or dephosphorylation. The conversion of gemcitabine by deamination into its inactive metabolite dFd-U is catalyzed by cytidine deaminase (CDD). 8 Cytoplasmic 5Ј nucleotidase (5NT) activity opposes that of dCK by dephosphorylating dFd-CMP, thereby preventing the production of the active form. 9 dFd-CTP is incorporated into DNA by replication synthesis in the C sites of the growing DNA strand. 10 Once incorporated into the DNA strand, an additional natu...

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“…In vitro studies have demonstrated that cancer cells may become relatively resistant to paclitaxel through a variety of mechanisms: 1) increased drug efflux that results from up-regulation of either mdr-1 gene 29,108 or some other membrane transporters; 36 2) mutation of amino acid residues in ␤-tubulin, which abolishes paclitaxel binding; 109 3) differential expression of various tubulin isotypes; 110 4) mutations of caspases in cancer cells, such as those in prostate carcinoma PC-3 cells 111 and in breast carcinoma MCF-7 cells; 112 and 5) up-regulation of the antiapoptotic Bcl-2 family members, such as Bcl-2 30 and Bcl-X L , 31 and/or down-regulation of the proapoptotic Bax. 113 …”

Section: Mechanisms Of Resistance To Paclitaxel Treatmentmentioning

confidence: 99%

Paclitaxel-induced cell death

Wang

Soong

2000

Cancer

562

185

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Bcl-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells.

Cited by 46 publications

References 0 publications

Artemin Stimulates Radio- and Chemo-resistance by Promoting TWIST1-BCL-2-dependent Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

Artemin Stimulates Radio- and Chemo-resistance by Promoting TWIST1-BCL-2-dependent Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

Expression of a non‐functional p53 affects the sensitivity of cancer cells to gemcitabine

Paclitaxel-induced cell death

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