Lin Jiumao, Shen Aling, Chen Hongwei, Liao Jun, Xu Teng, Liu Liya, Lin Jing, Peng Jun
Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
BMC Cancer. 2014 Sep 30;14:729. doi: 10.1186/1471-2407-14-729.
The development of hepatic cancer is tightly regulated by multiple intracellular signaling pathways. Therefore, most currently-used anti-tumor agents, which typically target single intracellular pathway, might not always be therapeutically effective. Additionally, long-term use of these agents probably generates drug resistance and unacceptable adverse effects. These problems increase the necessity for the development of new chemotherapeutic approaches. Nitidine chloride (NC), a natural benzophenanthridine alkaloid, has been shown to inhibit cancer growth via induction of cell apoptosis and suppression of cancer angiogenesis. But the precise mechanisms of its tumorcidal activity are not well understood.
To further elucidate the precise mechanisms of its anti-tumor activity, using a hepatic cancer mouse xenograft model, the human hepatic cancer cell lines (HepG2, HCCLM3, Huh7), and umbilical vein endothelial cells (HUVEC), here we evaluate the effect of NC on tumor growth in vivo and in vitro and investigated the underlying molecular mechanisms.
We found that NC treatment resulted in significant decrease in tumor volume and tumor weight respectively, but didn't affect body weight changes. Additionally, NC treatment dose- and time-dependently reduced the cell viability of all three hepatic cell lines. Moreover, NC suppressed the activation of STAT3, ERK and SHH pathways; and altered the expression of critical target genes including Bcl-2, Bax, Cyclin D1, CDK4, VEGF-A and VEGFR2. These molecular effects resulted in the promotion of apoptosis, inhibition of cell proliferation and tumor angiogenesis.
Our findings suggest that NC possesses a broad range of anti-cancer activities due to its ability to affect multiple intracellular targets, suggesting that NC could be a novel multi-potent therapeutic agent for the treatment of hepatic cancer and other cancers.
肝癌的发生受到多种细胞内信号通路的严格调控。因此，目前大多数常用的抗肿瘤药物，通常靶向单一细胞内通路，可能并不总是具有治疗效果。此外，长期使用这些药物可能会产生耐药性和不可接受的副作用。这些问题增加了开发新的化疗方法的必要性。氯化两面针碱（NC）是一种天然的苯并菲啶生物碱，已被证明可通过诱导细胞凋亡和抑制肿瘤血管生成来抑制癌症生长。但其杀肿瘤活性的确切机制尚不清楚。
为了进一步阐明其抗肿瘤活性的确切机制，我们使用肝癌小鼠异种移植模型、人肝癌细胞系（HepG2、HCCLM3、Huh7）和脐静脉内皮细胞（HUVEC），评估了NC对体内外肿瘤生长的影响，并研究了其潜在的分子机制。
我们发现，NC治疗分别导致肿瘤体积和肿瘤重量显著降低，但不影响体重变化。此外，NC治疗剂量和时间依赖性地降低了所有三种肝癌细胞系的细胞活力。此外，NC抑制了STAT3、ERK和SHH通路的激活；并改变了包括Bcl-2、Bax、Cyclin D1、CDK4、VEGF-A和VEGFR2在内的关键靶基因的表达。这些分子效应导致了细胞凋亡的促进、细胞增殖和肿瘤血管生成的抑制。
我们的研究结果表明，NC由于其能够影响多个细胞内靶点而具有广泛的抗癌活性，这表明NC可能是一种新型的多效治疗剂，可用于治疗肝癌和其他癌症。
