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Inhibition of Phosphatidylinositol 3-kinase (PI3K) Signaling Synergistically Potentiates Antitumor Efficacy of Paclitaxel and Overcomes Paclitaxel-Mediated Resistance in Cervical Cancer
- Source :
- International Journal of Molecular Sciences, Volume 20, Issue 14, International Journal of Molecular Sciences, Vol 20, Iss 14, p 3383 (2019)
- Publication Year :
- 2019
- Publisher :
- MDPI, 2019.
-
Abstract
- Acquired paclitaxel (PTX) resistance limits its effectiveness and results in advanced cancer progression. This review investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. It was established paclitaxel-resistant cell lines (PTX-R ME180/PTX-R HeLa) and determined the combination index for paclitaxel and PI3K inhibitors (BYL-719/ LY294002) by tetrazolium dye assay. Flow cytometry was used to detect the cell cycle and apoptosis. Migration and invasion were explored by wound healing and transwell assays. Genes related to multiple pathways were assessed by a western blot. It was found that the PI3K pathway was significantly activated in paclitaxel-resistant HeLa and ME180 cells compared to parental cells. PTX + PI3K inhibitor combined therapy showed a synergistic effect by strengthening paclitaxel-induced S and G2M arrest in PTX-R cell sublines by the inactivation of cyclin A1, cyclin B1, cyclin E, and Cdc2 expression. Moreover, combination therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, and cleavage of poly-(ADP-ribose) polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasion by targeting &beta<br />catenin and matrix metalloproteinase-2/9. The authors suggest that the combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.
- Subjects :
- Cyclin E
Paclitaxel
cervical cancer
Class I Phosphatidylinositol 3-Kinases
Uterine Cervical Neoplasms
Antineoplastic Agents
Apoptosis
PI3K inhibitor
Catalysis
Article
combination therapy
Inorganic Chemistry
HeLa
lcsh:Chemistry
chemistry.chemical_compound
Cell Line, Tumor
Humans
LY294002
Physical and Theoretical Chemistry
Enzyme Inhibitors
Cyclin B1
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
Cyclin-dependent kinase 1
biology
Organic Chemistry
Cell Cycle
Genetic Variation
Drug Synergism
General Medicine
Cell cycle
biology.organism_classification
invasion
Computer Science Applications
paclitaxel resistance
chemistry
lcsh:Biology (General)
lcsh:QD1-999
Drug Resistance, Neoplasm
Cancer research
Female
Phosphatidylinositol 3-Kinase
Cyclin A1
Proto-Oncogene Proteins c-akt
DNA Damage
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 20
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....8d4a2b4cf6f2ec200ba704c2be73bb52