Prostate cancer is a multi-focal disease that can be treated using surgery, radiation, androgen deprivation, and chemotherapy, depending on its presentation. Standard dose-escalated radiation therapy (RT) in the range of 70–80 Gray (GY) is a standard treatment option for prostate cancer. It could be used at different phases of the disease (e.g., as the only primary treatment when the cancer is confined to the prostate gland, combined with other therapies, or as an adjuvant treatment after surgery). Unfortunately, RT for prostate cancer is associated with gastro-intestinal and genitourinary toxicity. We have previously reported that the metabolic modulator lonidamine (LND) produces cancer sensitization through tumor acidification and de-energization in diverse neoplasms. We hypothesized that LND could allow lower RT doses by producing the same effect in prostate cancer, thus reducing the detrimental side effects associated with RT. Using the Seahorse XFe96 and YSI 2300 Stat Plus analyzers, we corroborated the expected LND-induced intracellular acidification and de-energization of isolated human prostate cancer cells using the PC3 cell line. These results were substantiated by non-invasive31P magnetic resonance spectroscopy (MRS), studying PC3 prostate cancer xenografts treated with LND (100 mg/kg, i.p.). In addition, we found that LND significantly increased tumor lactate levels in the xenografts using1H MRS non-invasively. Subsequently, LND was combined with radiation therapy in a growth delay experiment, where we found that 150 µM LND followed by 4 GY RT produced a significant growth delay in PC3 prostate cancer xenografts, compared to either control, LND, or RT alone. We conclude that the metabolic modulator LND radio-sensitizes experimental prostate cancer models, allowing the use of lower radiation doses and diminishing the potential side effects of RT. These results suggest the possible clinical translation of LND as a radio-sensitizer in patients with prostate cancer.
前列腺癌是一种多灶性疾病，根据其临床表现可采用手术、放疗、雄激素剥夺和化疗等多种治疗方式。标准剂量递增放疗（70-80戈瑞）是前列腺癌的标准治疗方案，可在疾病不同阶段应用（如作为局限性前列腺癌的单一主要治疗手段，或与其他疗法联合使用，亦或作为术后辅助治疗）。然而前列腺癌放疗常伴随胃肠道与泌尿生殖系统毒性反应。我们既往研究发现，代谢调节剂氯尼达明通过肿瘤酸化和能量耗竭机制可增强多种肿瘤的放射敏感性。本研究提出假说：氯尼达明可能通过相同机制降低前列腺癌所需放疗剂量，从而减少放疗相关不良反应。通过Seahorse XFe96能量代谢分析仪和YSI 2300 Stat Plus生化分析仪，我们在PC3前列腺癌细胞系中证实了氯尼达明诱导的细胞内酸化及能量耗竭效应。采用无创性31P磁共振波谱技术对氯尼达明（100 mg/kg腹腔注射）处理的PC3前列腺癌移植瘤进行研究，进一步验证了上述发现。此外，通过1H磁共振波谱无创检测发现，氯尼达明显著提升了移植瘤的乳酸水平。在后续生长延缓实验中，氯尼达明与放疗联合应用显示：150 µM氯尼达明联合4戈瑞放疗方案，相较于对照组、单用氯尼达明或单用放疗组，能显著延缓PC3前列腺癌移植瘤的生长。本研究结论：代谢调节剂氯尼达明可增强实验性前列腺癌模型的放射敏感性，有助于降低放疗剂量并减少潜在副作用。这些发现为氯尼达明作为放射增敏剂在前列腺癌患者中的临床转化应用提供了理论依据。
肿瘤(癌症)患者之家