The combination effects of Shen-Ling-Bai-Zhu on promoting apoptosis of transplanted H₂₂ hepatocellular carcinoma in mice receiving chemotherapy

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• 作者：Shengyan Xi^a ; ^b ; ¹ ; ^{xishengyan@xmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Ying Peng^a ; ¹ ; Gerald Y. Minuk^c ; Mengmeng Shi^a ; Biqian Fu^a ; Jiaqi Yang^d ; Qian Li^c ; Yuewen Gong^d ; Lifeng Yue^e ; Lili Li^a ; Jinhua Guo^a ; Yang Peng^d ; Yanhui Wang^a
• 关键词：SLBZP ; Shen-Ling-Bai-Zhu Powder ; TCM ; traditional Chinese medicine ; CTX ; Cytoxan ; NF-КB ; Nuclear Factor kappa B ; PDGF ; platelet-derived growth factor ; VEGF ; vascular endothelial growth factor ; Ang-1 ; angiogenin-1 ; Ang-2 ; angiogenin-2 ; Bcl-2 ; B-cell lymphoma-2 ; Bcl-xL ; B-cell lymphoma-extra large ; XIAP ; X-linked inhibitor of apoptosis ; HE ; hematoxylin and eosin ; ELISA ; enzyme-linked immunosorbent assay
• 刊名：Journal of Ethnopharmacology
• 出版年：2016
• 出版时间：22 August 2016
• 年：2016
• 卷：190
• 期：Complete
• 页码：1-12
• 全文大小：3145 K

文摘

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.

Aim of the study

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.

Materials and methods

Sixty-four adult mice developed HCC following subcutaneous inoculation with H₂₂ hepatocellular carcinoma cells. Seven days later, all received chemotherapy with CTX (200 mg/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, 1.5 g/kg), three with SLBZP (6.00, 3.00, 1.5 g/kg) plus CTX (20 mg/kg), one with CTX (20 mg/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.

Results

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.

Conclusions

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.