(ChemotherapyAdvisor) – Researchers at the University of Alberta, Edmonton, Alberta, Canada, have published a study that identifies a new mechanism of resistance for the commonly used chemotherapeutic agent paclitaxel.
The study, entitled “The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis”, was published in the March 19 issue of Oncogene. Although the anti-mitotic taxanes paclitaxel and docetaxel are widely used for the treatment of breast, ovarian, and lung cancers, their mechanism of resistance is not completely understood. It is known that paclitaxel induces apoptosis and also modulates autophagy, but the mechanism by which autophagy affects paclitaxel activity is unclear.
“We discovered that paclitaxel inhibited autophagy through two distinct mechanisms dependent on cell cycle stage,” the authors wrote. “In mitotic cells, paclitaxel blocked activation of the class 3 phosphatidyl inositol 3 kinase, Vps34, a critical initiator of autophagosome formation. In non-mitotic paclitaxel-treated cells, autophagosomes were generated but their movement and maturation was inhibited.”
When the researchers inhibited autophagosome formation either chemically or genetically, they diminished paclitaxel-induced cell death, leading the researchers to suggest that autophagosome accumulation sensitized cancer cells to paclitaxel toxicity. It was further observed that when primary breast tumors expressed diminished levels of autophagy-initiating genes, they were resistant to taxane therapy.
The researchers concluded that the chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis, suggesting possible mechanisms and prognostic markers of clinical taxane resistance.