title: Paclitaxel sensitivity of breast cancer cells requires efficient mitotic arrest and disruption of Bcl-xL/Bak interaction.
abstract: Taxanes are being used for the treatment of breast cancer. However, cancer cells frequently develop resistance to these drugs with the subsequent recurrence of the tumor. MDA-MB-231 and T-47D breast cancer cell lines were used to assess the effect of paclitaxel treatment on apoptosis and cell cycle, the possible mechanisms of paclitaxel resistance as well as the enhancement of paclitaxel-induced apoptosis based on its combination with phenylethyl isothiocyanate (PEITC). T-47D cells undergo apoptosis in response to paclitaxel treatment. The induction of apoptosis was associated with a robust mitotic arrest and the disruption of Bcl-xL/Bak interaction. By contrary, MDA-MB-231 cells were insensitive to paclitaxel-induced apoptosis and this was associated with a high percentage of cells that slip out of paclitaxel-imposed mitotic arrest and also with the maintenance of Bcl-xL/Bak interaction. The sequential treatment of MDA-MB-231 cells with PEITC followed by paclitaxel inhibited the slippage induced by paclitaxel and increased the apoptosis induction achieved with any of the drugs alone. In breast cancer tissues, high Bcl-xL expression was correlated with a shorter time of disease-free survival in patients treated with a chemotherapeutic regimen that contains paclitaxel, in a statistically significant way. Thus, resistance to paclitaxel in MDA-MB-231 cells is related to the inability to disrupt the Bcl-xL/Bak interaction and increased slippage. In this context, the combination of a drug that induces a strong mitotic arrest, such as paclitaxel, with another that inhibits slippage, such as PEITC, translates into increased apoptotic induction.
authors.affiliation: Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Avenida Manuel Siurot s/n, Seville 41013, Spain.
authors.forename: M Luz
authors.initials: ML
authors.lastname: Flores
authors.forename: Carolina
authors.initials: C
authors.lastname: Castilla
authors.forename: Rainiero
authors.initials: R
authors.lastname: Ávila
authors.forename: Manuel
authors.initials: M
authors.lastname: Ruiz-Borrego
authors.forename: Carmen
authors.initials: C
authors.lastname: Sáez
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Japón
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017879:Isothiocyanates; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C058305:phenethyl isothiocyanate; D017239:Paclitaxel