School of Pharmacy, Chengdu Medical College, Chengdu, China.
The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China.
Environ Toxicol. 2023 Dec;38(12):2894-2903. doi: 10.1002/tox.23924. Epub 2023 Aug 8.
Cancer stem cells (CSCs) play a key role in tumor cell growth, drug resistance, recurrence, and metastasis. Proanthocyanidins (PC) is widely existed in plants and endowed with powerful antioxidant and anti-aging effects. Interestingly, recent studies have found that PC exhibits the inhibitory effect on tumor growth. However, the role of PC in CSCs of colorectal cancer (CRC) and molecular mechanism remain unclear.
CCK-8, colony, and tumorsphere formation assay were used to evaluate cancer cell viability and stemness, respectively. Western blotting was used to detect the protein expression. Tumor xenograft experiments were employed to examine the tumorigenicity of CRC cells in nude mice.
PC decreased the proliferation of CRC cells (HT29 and HCT-116), and improved the sensitivity of CRC cells to oxaliplatin (L-OHP), as well as inhibited tumor growth in nude mice. Further studies showed that PC also down-regulated CSCs surface molecular and stemness transcriptional factors, while suppressed the formations of tumorspheres and cell colony in CRC. In addition, PC-impaired proteins expressions of p-GSK3β, β-catenin and DVL1-3. LiCl, an activator of the Wnt/β-catenin signaling, rescued PC-induced downregulation of CSCs markers, and reduction of tumorspheres and cell colony formation abilities in CRC cells. Furthermore, the effects of PC on inhibiting cell proliferation and enhancing L-OHP sensitivity were impaired by LiCl.
PC exerted an inhibitory effect on CSCs via Wnt/β-catenin in CRC, and may be a potential new class of natural drug for CRC treatment.
癌症干细胞（CSCs）在肿瘤细胞生长、耐药性、复发和转移中发挥关键作用。原花青素（PC）广泛存在于植物中，具有强大的抗氧化和抗衰老作用。有趣的是，最近的研究发现 PC 对肿瘤生长具有抑制作用。然而，PC 在结直肠癌（CRC）CSCs 中的作用及其分子机制尚不清楚。
CCK-8、集落和肿瘤球形成实验分别用于评估癌细胞活力和干性。Western blot 用于检测蛋白表达。肿瘤异种移植实验用于检测 CRC 细胞在裸鼠中的致瘤性。
PC 降低了 CRC 细胞（HT29 和 HCT-116）的增殖能力，并提高了 CRC 细胞对奥沙利铂（L-OHP）的敏感性，同时抑制了裸鼠肿瘤的生长。进一步的研究表明，PC 还下调了 CSCs 表面分子和干性转录因子，同时抑制了 CRC 中肿瘤球和细胞集落的形成。此外，PC 还损害了 p-GSK3β、β-catenin 和 DVL1-3 的蛋白表达。Wnt/β-catenin 信号通路的激活剂 LiCl 挽救了 PC 诱导的 CSCs 标志物下调以及 CRC 细胞肿瘤球和细胞集落形成能力降低。此外，LiCl 削弱了 PC 抑制细胞增殖和增强 L-OHP 敏感性的作用。
PC 通过 Wnt/β-catenin 在 CRC 中对 CSCs 发挥抑制作用，可能成为 CRC 治疗的一种有潜力的新型天然药物。
