Background: Colorectal cancer is one of the leading and most lethal neoplasms. Standard chemotherapy is ineffective, especially in metastatic cancer, and does not target cancer stem cells. A promising approach to improve cancer treatment is the combination therapy of standard cytostatic drugs with natural compounds. Several plant-derived compounds have been proven to possess anticancer properties, including the induction of apoptosis and inhibition of cancer invasion. This study was focused on investigating in vitro the combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic (LOVO) and stem-like (LOVO/DX) colon cancer cells.Methods: The genotoxic effects that drive cancer cells into death-inducing pathways and the ability to inhibit the migratory properties of cancer cells were evaluated. The γH2AX+ assay and Fast-Halo Assay (FHA) were used to evaluate genotoxic effects, the annexin-V apoptosis assay to rate the level of apoptosis, and the scratch test to assess antimigratory capacity.Results: The results showed that both combinations CPT-CEL and CPT-RSV improve general genotoxicity of CPT alone on metastatic cells and CSCs. However, the assessment of specific double-stranded breaks (DSBs) indicated a better efficacy of the CPT-CEL combination on LOVO cells and CPT-RSV in LOVO/DX cells. Interestingly, the combinations CPT-CEL and CPT-RSV did not improve the pro-apoptotic effect of CPT alone, with both LOVO and LOVO/DX cells suggesting activation of different cell death mechanisms. Furthermore, it was found that the combinations of CPT-CEL and CPT-RSV improve the inhibitory effect of camptothecin on cell migration.Conclusions: These findings suggest the potential utility of combining camptothecin with celastrol or resveratrol in the treatment of colon cancer, including more aggressive forms of the disease. So far, no studies evaluating the effects of combinations of these compounds have been published in the available medical databases.
背景：结直肠癌是最常见且致死率最高的恶性肿瘤之一。标准化疗方案疗效有限，尤其对转移性癌症效果不佳，且无法靶向癌症干细胞。将标准细胞抑制药物与天然化合物联合使用，是改善癌症治疗前景的一种策略。多种植物源化合物已被证实具有抗癌特性，包括诱导细胞凋亡和抑制癌症侵袭。本研究旨在体外探讨喜树碱（CPT）分别与雷公藤红素（CEL）或白藜芦醇（RSV）联用，作为靶向转移性（LOVO）和干细胞样（LOVO/DX）结肠癌细胞的潜在治疗策略。 方法：研究评估了驱动癌细胞进入死亡诱导通路的基因毒性效应及抑制癌细胞迁移能力的效果。采用γH2AX+检测和快速彗星试验（FHA）评估基因毒性效应，膜联蛋白V凋亡检测评估细胞凋亡水平，划痕实验评估抗迁移能力。 结果：研究显示，CPT-CEL与CPT-RSV两种联合方案均能增强CPT单药对转移性癌细胞和癌症干细胞的总体基因毒性。然而，特异性双链断裂（DSBs）评估表明，CPT-CEL联用对LOVO细胞效果更佳，而CPT-RSV联用对LOVO/DX细胞效果更好。值得注意的是，两种联合方案均未增强CPT单药的促凋亡效应，提示LOVO和LOVO/DX细胞可能激活了不同的细胞死亡机制。此外，研究发现CPT-CEL和CPT-RSV联合用药能增强喜树碱对细胞迁移的抑制作用。 结论：这些发现表明，喜树碱与雷公藤红素或白藜芦醇联合用药在结肠癌（包括更具侵袭性的疾病类型）治疗中具有潜在应用价值。迄今为止，现有医学数据库中尚未发表评估这些化合物联合作用效果的相关研究。
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