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. 2007 Apr 7;13(13):1989-94.
doi: 10.3748/wjg.v13.i13.1989.

Enhanced therapeutic effects of combined chemotherapeutic drugs and midkine antisense oligonucleotides for hepatocellular carcinoma

Li-Cheng Dai  1 , Xiang Wang, Xing Yao, Yong-Liang Lu, Jin-Liang Ping, Jian-Fang He
Affiliations

Enhanced therapeutic effects of combined chemotherapeutic drugs and midkine antisense oligonucleotides for hepatocellular carcinoma

Li-Cheng Dai et al. World J Gastroenterol. .

Abstract

Aim: To evaluate the effect of combined antisense oligonucleotides targeting midkine (MK-AS) and chemotherapeutic drugs [cisplatin(DDP), 5-fluorouracil (5-FU) and adriamycin (ADM)] on inhibition of HepG2 cell proliferation, and to analyze the efficacy of MK-AS used in combined ADM in in situ human hepatocellular carcinoma (HCC) model.

Methods: HepG2 cells were treated with MK-AS and/or chemotherapeutic drugs mediated by Lipofectin, and cell growth activity was determined by MTS assay. An in situ HCC model was used in this experiment. MK-AS, ADM and MK-AS + ADM were given intravenously for 20 d, respectively. The animal body weight and their tumor weight were measured to assess the effect of the combined therapy in vivo.

Results: Combined treatment with MK-AS reduced the IC50 of DDP, 5-FU and ADM in HepG2 cells. MK-AS significantly increased the inhibition rate of DDP, 5-FU and ADM. Additionally, synergism (Q 1.15) occurred at a lower concentration of ADM, 5-FU and DDP with combined MK-AS. Combined treatment with MK-AS and ADM resulted in the more growth inhibition on in situ human HCC model compared with treatment with chemotherapeutic drugs alone.

Conclusion: MK-AS increases the chemosensitivity in HepG2 cells and in situ human HCC model, and the combination of MK-AS and ADM has a much better in vitro and in vivo synergism.

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Figures

Figure 1
Figure 1
Analysis of combined effect of MK-AS and ADM (A), 5-FU (B) and DDP (C) in HepG2 cells. Each value represents the mean ± SD from triplicate determinations.
Figure 2
Figure 2
Q values for combined treatment of MK-AS and ADM (A), 5- FU (B) and DDP (C) in HepG2 cells. Q values were calculated from the dose-response curves shown in Figure 1 and analyzed by Zheng-Jun Jin’s method.
Figure 3
Figure 3
Tumor growth in situ human HCC model after treatment with MK-AS and/or ADM. CK: Treatment with saline; ADM: Treatment with ADM; MK-AS: Treatment with MK-AS; ADM + MK-AS: Combination of ADM with MK-AS. Each value represents the mean ± SD from 7 determinations.
Figure 4
Figure 4
The human HCC model animal weight after treatment with MK-AS and/or ADM. CK: Treatment with saline; ADM: Treatment with ADM; MK-AS: Treatment with MK-AS; ADM + MK-AS: Combination of ADM with MK-AS. Each value represents the mean ± SD from 7 determinations.
Figure 5
Figure 5
Effects of MK-AS and ADM on MK expression in in situ human hepatocellular carcinoma (HCC) model. A: Electrophoresis of RT-PCR products of MK gene and GAPDH gene, GAPDH is used as control; B: The total protein were separated by SDS gel electrophoresis, transferred to PVDF membranes, and blotted with anti-MK body. β-actin rabbit polyclonal antibodies was used as a loading control. CK: Treatment with saline; ADM: Treatment with ADM; MK-AS: Treatment with MK-AS; ADM + MK-AS: Combination of ADM with MK-AS.
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