Xi Shengyan, Peng Ying, Minuk Gerald Y, Shi Mengmeng, Fu Biqian, Yang Jiaqi, Li Qian, Gong Yuewen, Yue Lifeng, Li Lili, Guo Jinhua, Peng Yang, Wang Yanhui
Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China; Cancer Research Center of Xiamen University, Xiamen 361102, People's Republic of China.
Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, People's Republic of China.
J Ethnopharmacol. 2016 Aug 22;190:1-12. doi: 10.1016/j.jep.2016.05.055. Epub 2016 May 24.
Shen-Ling-Bai-Zhu Powder (SLBZP) is a classic traditional Chinese medical formula that has been used for several decades in the treatment of patients with gastrointestinal malignancies. Whether SLBZP is best employed as single agent or adjunctive therapy has yet to be determined as does the mechanism whereby SLBZP exerts its anti-tumor effects.
To investigate the effects of SLBZP alone and in combination with Cytoxan (CTX) on tumor growth, malignant cell apoptosis and Akt/Nuclear Factor kappa B (NF-КB) signaling in a murine model of hepatocellular carcinoma (HCC) receiving chemotherapy.
Sixty-four adult mice developed HCC following subcutaneous inoculation with H22 hepatocellular carcinoma cells. Seven days later, all received chemotherapy with CTX (200mg/kg) once. Mice were then randomized into eight study groups (N=8/group). Three groups were treated with different concentrations of SLBZP alone (6.00, 3.00, 1.5g/kg), three with SLBZP (6.00, 3.00, 1.5g/kg) plus CTX (20mg/kg), one with CTX (20mg/kg) alone (positive control), and one with physiologic saline (untreated, negative control). All groups were treated for 14 days. Tumor size, histology and serum or tissue levels and/or mRNA expression of PDGF-BB, VEGF, Ang-1, Ang-2, NF-КB, B-cell lymphoma-2 (Bcl-2); B-cell lymphoma-extra large (Bcl-xL); X-linked inhibitor of apoptosis (XIAP), Survivin, Caspase-3, Caspase-9, Caspase-7, Akt and phosphorylated Akt expression were documented at the end of treatment.
Compared to untreated negative controls, tumor sizes were decreased in the CTX alone, SLBZP (M)+CTX and SLBZP (H)+CTX groups (-52%,-53% and -58% respectively). Tumor cell density was decreased in all treated groups but most apparent in the SLBZP (H)+CTX group. Electron microscopic evidence of apoptosis was also most apparent in this group. Serum and/or tissue levels and expression of PDGF-BB, VEGF, Ang-1, Ang-2, their downstream signaling proteins and anti-apoptotic markers were lowest and pro-apoptotic markers highest in SLBZP (H)+CTX treated mice.
In this chemotherapy-induced animal model of HCC, SLBZP was most efficacious as adjunctive therapy and appears to act by inhibiting tumor growth promoters and anti-apoptotic proteins while enhancing pro-apoptotic proteins.
参苓白术散（SLBZP）是一种经典的中药方剂，已用于治疗胃肠道恶性肿瘤患者数十年。SLBZP是最佳作为单一药物还是辅助治疗尚未确定，其发挥抗肿瘤作用的机制也尚未明确。
研究SLBZP单独使用以及与环磷酰胺（CTX）联合使用对接受化疗的小鼠肝癌（HCC）模型中肿瘤生长、恶性细胞凋亡和Akt/核因子κB（NF-κB）信号传导的影响。
64只成年小鼠在皮下接种H22肝癌细胞后发生HCC。7天后，所有小鼠均接受一次CTX（200mg/kg）化疗。然后将小鼠随机分为8个研究组（每组n = 8）。3组分别单独用不同浓度的SLBZP（6.00、3.00、1.5g/kg）治疗，3组用SLBZP（6.00、3.00、1.5g/kg）加CTX（20mg/kg）治疗，1组单独用CTX（20mg/kg）治疗（阳性对照），1组用生理盐水治疗（未治疗，阴性对照）。所有组均治疗14天。在治疗结束时记录肿瘤大小、组织学以及血小板衍生生长因子-BB（PDGF-BB）、血管内皮生长因子（VEGF）、血管生成素-1（Ang-1）、血管生成素-2（Ang-2）、NF-κB、B细胞淋巴瘤-2（Bcl-2）、B细胞淋巴瘤-超大（Bcl-xL）、X连锁凋亡抑制蛋白（XIAP）、生存素、半胱天冬酶-3（Caspase-3）、半胱天冬酶-9（Caspase-9）、半胱天冬酶-7（Caspase-7）、Akt和磷酸化Akt的血清或组织水平和/或mRNA表达。
与未治疗的阴性对照相比，单独使用CTX、SLBZP（中剂量）+CTX和SLBZP（高剂量）+CTX组的肿瘤大小减小（分别为-52%、-53%和-58%）。所有治疗组的肿瘤细胞密度均降低，但在SLBZP（高剂量）+CTX组中最明显。该组中凋亡的电子显微镜证据也最明显。在SLBZP（高剂量）+CTX治疗的小鼠中，PDGF-BB、VEGF、Ang-1、Ang-2及其下游信号蛋白和抗凋亡标志物的血清和/或组织水平及表达最低，促凋亡标志物最高。
在这个化疗诱导的HCC动物模型中，SLBZP作为辅助治疗最有效，其作用似乎是通过抑制肿瘤生长促进因子和抗凋亡蛋白，同时增强促凋亡蛋白。
