Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
Materia Therapeutics, Las Vegas, NV, USA.
Commun Biol. 2024 Nov 27;7(1):1581. doi: 10.1038/s42003-024-07268-1.
Pancreatic cancer remains one of the most lethal malignancies, with limited treatment options and poor prognosis. A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells. Our results demonstrate that inhibition of autophagy using hydroxychloroquine (HCQ) enhanced the oxaliplatin-induced apoptotic cell death in pancreatic cancer cells exposed to mechanical stress. The combined treatment of HCQ with losartan, a known modulator of mechanical abnormalities in tumors, synergistically enhanced the therapeutic efficacy of oxaliplatin in murine pancreatic tumor models. Furthermore, our study revealed that the use of HCQ enhanced the efficacy of losartan to alleviate mechanical stress levels and restore blood vessel integrity beyond its role in autophagy modulation. These findings underscore the potential of co-targeting mechanical stresses and autophagy as a promising therapeutic strategy to overcome drug resistance and increase chemotherapy efficacy.
胰腺癌仍然是最致命的恶性肿瘤之一，治疗选择有限，预后不良。胰腺癌患者的一个共同特征是生物力学改变的肿瘤微环境（TME），它是肿瘤内部升高的机械应力的原因之一。尽管大量研究已经阐明了机械应力对癌细胞增殖和迁移的影响，但尚未研究它如何影响癌细胞对药物的敏感性。在这里，我们证明机械应力会触发自噬激活，这与胰腺癌细胞对奥沙利铂治疗的耐药性增加有关。我们的结果表明，在机械应力下，使用羟氯喹（HCQ）抑制自噬会增强奥沙利铂诱导的胰腺癌细胞凋亡。HCQ 与氯沙坦（一种已知可调节肿瘤机械异常的药物）联合治疗可协同增强奥沙利铂在小鼠胰腺肿瘤模型中的治疗效果。此外，我们的研究表明，HCQ 的使用增强了氯沙坦缓解机械应激水平和恢复血管完整性的效果，超出了其在自噬调节中的作用。这些发现强调了共同靶向机械应激和自噬作为一种有前途的治疗策略的潜力，以克服耐药性并提高化疗效果。
