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Abstract：
BACKGROUND: Therapy-induced senescent cancer and stromal cells secrete cytokines and growth factors to promote tumor progression. Therefore, senescent cells may be novel targets for tumor treatment. Near-infrared photoimmunotherapy (NIR-PIT) is a highly tumor-selective therapy that employs conjugates of a molecular-targeting antibody and photoabsorber. Thus, NIR-PIT has the potential to be applied as a novel senolytic therapy. This study aims to investigate the efficacy of NIR-PIT treatment on senescent cancer and stromal cells.
METHODS: Two cancer cell lines (human lung adenocarcinoma A549 cells and human pancreatic cancer MIA PaCa-2 cells) and two normal cell lines (mouse fibroblast transfected with human epidermal growth factor receptor 2 [HER2] cells and human fibroblast WI38 cells) were used. The cytotoxicity of NIR-PIT was evaluated using anti-epidermal growth factor receptor (EGFR) antibody panitumumab and anti-HER2 antibody transtuzumab.
RESULTS: Cellular senescence was induced in A549 and MIA PaCa-2 cells by 10 Gy γ-irradiation. The up-regulation of cellular senescence markers and characteristic morphological changes in senescent cells, including enlargement, flattening, and multinucleation, were observed in cancer cells after 5 days of γ-irradiation. Then, NIR-PIT targeting EGFR was performed on these senescent cancer cells. The NIR-PIT induced morphological changes, including bleb formation, swelling, and the inflow of extracellular fluid, and induced a significant decrease in cellular viability. These results suggested that NIR-PIT may induce cytotoxicity using the same mechanism in senescent cancer cells. In addition, similar morphological changes were also induced in radiation-induced senescent 3T3-HER2 fibroblasts by NIR-PIT targeting human epidermal growth factor receptor 2.
CONCLUSIONS: NIR-PIT eliminates both senescent cancer and stromal cells in vitro suggesting it may be a novel strategy for tumor treatment.
METHODS: Two cancer cell lines (human lung adenocarcinoma A549 cells and human pancreatic cancer MIA PaCa-2 cells) and two normal cell lines (mouse fibroblast transfected with human epidermal growth factor receptor 2 [HER2] cells and human fibroblast WI38 cells) were used. The cytotoxicity of NIR-PIT was evaluated using anti-epidermal growth factor receptor (EGFR) antibody panitumumab and anti-HER2 antibody transtuzumab.
RESULTS: Cellular senescence was induced in A549 and MIA PaCa-2 cells by 10 Gy γ-irradiation. The up-regulation of cellular senescence markers and characteristic morphological changes in senescent cells, including enlargement, flattening, and multinucleation, were observed in cancer cells after 5 days of γ-irradiation. Then, NIR-PIT targeting EGFR was performed on these senescent cancer cells. The NIR-PIT induced morphological changes, including bleb formation, swelling, and the inflow of extracellular fluid, and induced a significant decrease in cellular viability. These results suggested that NIR-PIT may induce cytotoxicity using the same mechanism in senescent cancer cells. In addition, similar morphological changes were also induced in radiation-induced senescent 3T3-HER2 fibroblasts by NIR-PIT targeting human epidermal growth factor receptor 2.
CONCLUSIONS: NIR-PIT eliminates both senescent cancer and stromal cells in vitro suggesting it may be a novel strategy for tumor treatment.
摘要：
背景：治疗诱导的衰老癌症和基质细胞分泌细胞因子和生长因子以促进肿瘤进展。因此,衰老细胞可能是肿瘤治疗的新靶点。近红外光免疫疗法（NIR-PIT）是一种高度肿瘤选择性的疗法，采用分子靶向抗体和光吸收剂的缀合物。因此，NIR-PIT具有作为新型抗衰老疗法应用的潜力。本研究旨在探讨NIR-PIT治疗对衰老癌症和基质细胞的疗效。
方法：使用两种癌细胞系（人肺腺癌A549细胞和人胰腺癌MIAPaCa-2细胞）和两种正常细胞系（人表皮生长因子受体2[HER2]细胞和人成纤维细胞WI38细胞转染的小鼠成纤维细胞）。使用抗表皮生长因子受体(EGFR)抗体帕尼单抗和抗HER2抗体曲妥珠单抗评估NIR-PIT的细胞毒性。
结果：通过10Gyγ射线照射诱导A549和MIAPaCa-2细胞衰老。细胞衰老标志物的上调和衰老细胞的特征性形态变化,包括扩大，展平,和多核化，在γ射线照射5天后在癌细胞中观察到。然后，在这些衰老癌细胞上进行靶向EGFR的NIR-PIT。NIR-PIT诱导的形态学改变,包括气泡形成，肿胀,和细胞外液的流入，并诱导细胞活力的显著降低。这些结果表明，NIR-PIT可能在衰老的癌细胞中使用相同的机制诱导细胞毒性。此外,靶向人表皮生长因子受体2的NIR-PIT在辐射诱导的衰老3T3-HER2成纤维细胞中也诱导了类似的形态学变化.
结论：NIR-PIT在体外消除了衰老的癌症和基质细胞，这表明它可能是肿瘤治疗的新策略。
方法：使用两种癌细胞系（人肺腺癌A549细胞和人胰腺癌MIAPaCa-2细胞）和两种正常细胞系（人表皮生长因子受体2[HER2]细胞和人成纤维细胞WI38细胞转染的小鼠成纤维细胞）。使用抗表皮生长因子受体(EGFR)抗体帕尼单抗和抗HER2抗体曲妥珠单抗评估NIR-PIT的细胞毒性。
结果：通过10Gyγ射线照射诱导A549和MIAPaCa-2细胞衰老。细胞衰老标志物的上调和衰老细胞的特征性形态变化,包括扩大，展平,和多核化，在γ射线照射5天后在癌细胞中观察到。然后，在这些衰老癌细胞上进行靶向EGFR的NIR-PIT。NIR-PIT诱导的形态学改变,包括气泡形成，肿胀,和细胞外液的流入，并诱导细胞活力的显著降低。这些结果表明，NIR-PIT可能在衰老的癌细胞中使用相同的机制诱导细胞毒性。此外,靶向人表皮生长因子受体2的NIR-PIT在辐射诱导的衰老3T3-HER2成纤维细胞中也诱导了类似的形态学变化.
结论：NIR-PIT在体外消除了衰老的癌症和基质细胞，这表明它可能是肿瘤治疗的新策略。
