Laboratory of Radiation Biophysics and Radiobiology, Department of Physics, University of Pavia, 27100 Pavia, Italy.
Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.
Int J Mol Sci. 2023 Feb 3;24(3):2983. doi: 10.3390/ijms24032983.
Colorectal cancer (CRC) is the most prominent form of colon cancer for both incidence (38.7 per 100,000 people) and mortality (13.9 per 100,000 people). CRC's poor response to standard therapies is linked to its high heterogeneity and complex genetic background. Dysregulation or depletion of the tumor suppressor p53 is involved in CRC transformation and its capability to escape therapy, with p53 cancer subtypes known, in fact, to have a poor prognosis. In such a context, new therapeutic approaches aimed at reducing CRC proliferation must be investigated. In clinical practice, CRC chemotherapy is often combined with radiation therapy with the aim of blocking the expansion of the tumor mass or removing residual cancer cells, though contemporary targeting of amino acid metabolism has not yet been explored. In the present study, we used the p53 Caco-2 model cell line to evaluate the effect of a possible combination of radiation and L-Asparaginase (L-ASNase), a protein drug that blocks cancer proliferation by impairing asparagine and glutamine extracellular supply. When L-ASNase was administered immediately after IR, we observed a reduced proliferative capability, a delay in DNA-damage response and a reduced capability to adhere and migrate. Our data suggest that a correctly timed combination of X-rays and L-ASNase treatment could represent an advantage in CRC therapy.
结直肠癌（CRC）是发病率（38.7/10 万人）和死亡率（13.9/10 万人）最高的结肠癌形式。CRC 对标准疗法反应不佳与其高度异质性和复杂的遗传背景有关。肿瘤抑制因子 p53 的失调或耗竭参与了 CRC 的转化及其逃避治疗的能力，事实上，p53 癌症亚型的预后较差。在这种情况下，必须研究旨在减少 CRC 增殖的新治疗方法。在临床实践中，CRC 化疗通常与放射治疗联合使用，目的是阻止肿瘤体积的扩大或去除残留的癌细胞，尽管目前尚未探索针对氨基酸代谢的靶向治疗。在本研究中，我们使用 p53 Caco-2 模型细胞系来评估放射治疗与 L-天冬酰胺酶（L-ASNase）联合应用的可能性，L-ASNase 是一种通过损害天冬酰胺和谷氨酰胺的细胞外供应来阻止癌症增殖的蛋白药物。当 L-ASNase 在 IR 后立即给药时，我们观察到增殖能力降低、DNA 损伤反应延迟以及粘附和迁移能力降低。我们的数据表明，X 射线和 L-ASNase 治疗的正确时间组合可能代表 CRC 治疗的优势。
