Inhibition of paclitaxel-induced proteasome activation influences paclitaxel cytotoxicity in breast cancer cells in a sequence-dependent manner.
Although the anti-tumour effects of paclitaxel result mainly from mitotic arrest, recent evidences suggest alternative mechanisms of cytotoxicity. Cell cycle, cell death, and gene expression assays were used to understand the molecular mechanisms of paclitaxel cytotoxicity in breast cancer cells. G(2)/M cell cycle arrest and cell death coincided with the regulation of genes involved in cell death, cell cycle control, microtubule-based processes, oxidative stress, and ubiquitin-proteasome system. Induction of proteasome genes was also correlated with an accumulation of protein for proteasome subunits. Furthermore, a schedule-dependent regulation of paclitaxel-induced cytotoxicity was observed after combining paclitaxel and the proteasome inhibitor MG132. Proteasome inhibition after paclitaxel exposure induced the highest rate of growth inhibition and apoptosis, with no effect on mitotic arrest. These findings give support to clinical combinations of taxanes with proteasome inhibitors, outlining the importance of considering the sequence when designing such regimens.
Hernández-Vargas
Héctor
H
Breast and Gynaecological Cancer Group, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
von Kobbe
Cayetano
C
Sánchez-Estévez
Carolina
C
Julián-Tendero
Mercedes
M
Palacios
José
J
Moreno-Bueno
Gema
G
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors
D007976:Leupeptins; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; D017239:Paclitaxel; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde