Radioresistance Mechanisms in Prostate Cancer Cell Lines Surviving Ultra-Hypo-Fractionated EBRT: Implications and Possible Clinical Applications.
Silvia SideriFrancesco PetragnanoRoberto MaggioSimonetta PetrungaroAngiolina CatizoneLuisa GesualdiViviana De MartinoGiulia BattafaranoAndrea Del FattoreDomenico LiguoroPaola De CesarisAntonio FilippiniFrancesco MaramponAnna RiccioliPublished in: Cancers (2022)
The use of a higher dose per fraction to overcome the high radioresistance of prostate cancer cells has been unsuccessfully proposed. Herein, we present PC3 and DU-145, castration-resistant prostate cancer cell lines that survived a clinically used ultra-higher dose per fraction, namely, radioresistant PC3 and DU-145 cells (PC3RR and DU-145RR). Compared to PC3, PC3RR showed a higher level of aggressive behaviour, with enhanced clonogenic potential, DNA damage repair, migration ability and cancer stem cell features. Furthermore, compared to PC3, PC3RR more efficiently survived further radiation by increasing proliferation and down-regulating pro-apoptotic proteins. No significant changes of the above parameters were described in DU-145RR, suggesting that different prostate cancer cell lines that survive ultra-higher dose per fraction do not display the same grade of aggressive phenotype. Furthermore, both PC3RR and DU-145RR increased antioxidant enzymes and mesenchymal markers. Our data suggest that different molecular mechanisms could be potential targets for future treatments plans based on sequential strategies and synergistic effects of different modalities, possibly in a patient-tailored fashion. Moreover, PC3RR cells displayed an increase in specific markers involved in bone remodeling, indicating that radiotherapy selects a PC3 population capable of migrating to secondary metastatic sites. Finally, PC3RR cells showed a better sensitivity to Docetaxel as compared to native PC3 cells. This suggests that a subset of patients with castration-resistant metastatic disease could benefit from upfront Docetaxel treatment after the failure of radiotherapy.
Keyphrases
- prostate cancer
- dna damage
- induced apoptosis
- small cell lung cancer
- squamous cell carcinoma
- oxidative stress
- stem cells
- high resolution
- radiation therapy
- cancer stem cells
- radical prostatectomy
- radiation induced
- bone marrow
- drug delivery
- cell death
- signaling pathway
- case report
- dna repair
- electronic health record
- climate change
- bone mineral density
- endoplasmic reticulum stress
- health insurance
- artificial intelligence
- replacement therapy