Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
Shawnee Mission School District Center for Academic Achievement, Kansas City, KS, 66204, USA.
Sci Rep. 2020 Jan 28;10(1):1290. doi: 10.1038/s41598-020-57940-9.
Cancer stem cells (CSCs) have the ability to self-renew and induce drug resistance and recurrence in colorectal cancer (CRC). As current chemotherapy doesn't eliminate CSCs completely, there is a need to identify novel agents to target them. We investigated the effects of cucurbitacin B (C-B) or I (C-I), a natural compound that exists in edible plants (bitter melons, cucumbers, pumpkins and zucchini), against CRC. C-B or C-I inhibited proliferation, clonogenicity, induced G/M cell-cycle arrest and caspase-mediated-apoptosis of CRC cells. C-B or C-I suppressed colonosphere formation and inhibited expression of CD44, DCLK1 and LGR5. These compounds inhibited notch signaling by reducing the expression of Notch 1-4 receptors, their ligands (Jagged 1-2, DLL1,3,4), γ-secretase complex proteins (Presenilin 1, Nicastrin), and downstream target Hes-1. Molecular docking showed that C-B or C-I binds to the ankyrin domain of Notch receptor, which was confirmed using the cellular thermal shift assay. Finally, C-B or C-I inhibited tumor xenograft growth in nude mice and decreased the expression of CSC-markers and notch signaling proteins in tumor tissues. Together, our study suggests that C-B and C-I inhibit colon cancer growth by inhibiting Notch signaling pathway.
癌症干细胞（CSCs）具有自我更新的能力，并在结直肠癌（CRC）中诱导耐药和复发。由于目前的化疗不能完全消除 CSCs，因此需要寻找新的药物来靶向它们。我们研究了天然化合物葫芦素 B（C-B）或 I（C-I）对 CRC 的作用，这种化合物存在于食用植物（苦瓜、黄瓜、南瓜和西葫芦）中。C-B 或 C-I 抑制 CRC 细胞的增殖、集落形成、诱导 G/M 细胞周期阻滞和半胱天冬酶介导的细胞凋亡。C-B 或 C-I 抑制类器官形成并抑制 CD44、DCLK1 和 LGR5 的表达。这些化合物通过降低 Notch1-4 受体、其配体（Jagged1-2、DLL1、3、4）、γ-分泌酶复合物蛋白（早老素 1、Nicastrin）和下游靶标 Hes-1 的表达来抑制 Notch 信号通路。分子对接表明 C-B 或 C-I 结合到 Notch 受体的锚蛋白结构域，这一点通过细胞热转移测定得到了证实。最后，C-B 或 C-I 抑制裸鼠肿瘤异种移植的生长，并降低肿瘤组织中 CSC 标志物和 Notch 信号通路蛋白的表达。总之，我们的研究表明 C-B 和 C-I 通过抑制 Notch 信号通路抑制结肠癌的生长。
