Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
Int J Mol Sci. 2020 Nov 10;21(22):8447. doi: 10.3390/ijms21228447.
Hypofractionation is currently considered a valid alternative to conventional radiotherapy for the treatment of patients with organ-confined prostate cancer. Recent data have demonstrated that extreme hypofractionation, which involves the use of a high radiation dose per delivered fraction and concomitant reduction of sessions, is a safe and effective treatment, even though its radiobiological rationale is still lacking. The present work aims to investigate the biological basis sustaining this approach and to evaluate the potential of a hypofractionated regimen in combination with androgen deprivation therapy, one of the major standards of care for prostate cancer. Findings show that androgen receptor (AR) modulation, by use of androgens and antiandrogens, has a significant impact on cell survival, especially in hypoxic conditions (4% O). Subsequent experiments have revealed that AR activity as a transcription factor is involved in the onset of malignant senescence-associated secretory phenotype (SASP) and activation of DNA repair cascade. In particular, we found that AR stimulation in hypoxic conditions promotes the enhanced transcription of gene, the cornerstone kinase of the DNA damage repair genes. Together, these data provide new potential insights to justify the use of androgen deprivation therapy, in particular with second-generation anti-androgens such as enzalutamide, in combination with radiotherapy.
适形放疗是目前治疗局限性前列腺癌的一种有效替代方法。最近的数据表明，超分割放疗是一种安全有效的治疗方法，其每一分次给予的高剂量放疗和同时减少治疗次数，尽管其放射生物学原理仍有待进一步研究。本研究旨在探讨支持这种方法的生物学基础，并评估联合雄激素剥夺疗法（前列腺癌的主要治疗标准之一）的超分割治疗方案的潜力。研究结果表明，雄激素受体（AR）的调节，无论是使用雄激素还是抗雄激素，对细胞存活都有显著影响，尤其是在低氧条件下（4% O）。随后的实验表明，作为转录因子的 AR 活性参与了恶性衰老相关分泌表型（SASP）的发生和 DNA 修复级联的激活。特别是，我们发现 AR 在低氧条件下的刺激促进了基因的转录，该基因是 DNA 损伤修复基因的关键激酶。总之，这些数据为联合使用雄激素剥夺疗法，特别是联合第二代抗雄激素药物如恩扎鲁胺进行放疗提供了新的潜在依据。
