Date Published: May 3, 2018
Author(s): Mei Lin, Chenglin Zhou, Junxing Huang, Weizhong Tian, Hong Yu, Xingmao Jiang, Jun Ye, Ting Guo, Yujuan Shi, Yanhong Xiao, Xuefeng Bian, Xiaoqian Feng.
Our previous findings showed a good therapeutic effect of the combination of suicide gene HSV-TK, nuclide 131I, and magnetic fluid hyperthermia (MFH) on hepatoma by using magnetic nanoparticles as linkers, far better than any monotherapy involved, with no adverse effects. This combination therapy might be an eligible strategy to treat hepatic cancer. However, it is not clear how the combination regimen took the therapeutic effects. In the current study, to explore the possible mechanisms of radionuclide-gene therapy combined with MFH to treat hepatoma at tissue, cellular, and molecular levels and to provide theoretical and experimental data for its clinical application, we examined the apoptosis induction of the combination therapy and investigated the expression of the proteins related to apoptosis such as survivin, livin, bcl-2, p53, and nucleus protein Ki67 involved in cell proliferation, detected VEGF, and MVD involved in angiogenesis of tumor tissues and analyzed the pathologic changes after treatment. The results showed that the combination therapy significantly induced the hepatoma cell apoptosis. The expression of survivin, VEGF, bcl-2, p53, livin, Ki67, and VEGF proteins and microvascular density (MVD) were all decreased after treatment. The therapeutic mechanisms may be involved in the downregulation of Ki67 expression leading to tumor cell proliferation repression and inhibition of survivin, bcl-2, p53, and livin protein expression inducing tumor cell apoptosis, negatively regulating VEGF protein expression, and reducing vascular endothelial cells, which results in tumor angiogenesis inhibition and microvascular density decrease and tumor cell necrosis. These findings offer another basic data support and theoretical foundation for the clinical application of the combination therapy.
As we all know, cancer has become the leading killer that endangers human health, with the highest morbidity and mortality. Undoubtedly, radiotherapy, chemotherapy, thermotherapy, and biotherapy all contribute to antitumor treatment to a great extent, but each has its own advantages and disadvantages, and any of them can hardly cure cancer thoroughly. Inspiring, comprehensive treatment, a joint therapeutic strategy based on multidiscipline and (or) multimethod by a specific way in view of their respective properties, has shown a great potential for malignancy treatment. It is not a simple overlap of some protocols but is put into use rationally to complement each other’s advantages, resulting in an effective synergism . Studies have shown that the combination of more than two therapeutic regimens can get better antitumor effects than any of the monotherapies involved [1–5]. In our previous study, we organically combined suicide gene, internal irradiation of nuclide, and magnetic fluid hyperthermia (MFH) to treat hepatoma by employing magnetic nanoparticles as hinges. In detail, pHRE-Egr1-HSV-TK was transfected into hepatoma cells by using PEI-Mn0.5Zn0.5Fe2O4 nanoparticles (PEI-MZF-NPs) as the gene transfer vector, and subsequently 131I-antiAFP McAb-GCV-BSA-NPs were intervened into hepatoma, and then the tumors were directionally heated in an alternating magnetic field by adopting PEI-MZF-NPs as magnetic media. Thus, while 131I and hyperthermia killing tumor cells, nuclide irradiation enabled the Egr1 promotor to induce HSV-TK gene to express, and the expression could be especially enhanced by HRE in hypoxic solid cancer, causing a multiple targeted killing effect of genes, radionuclide and hyperpyrexia against hepatoma. The results demonstrated that the radionuclide-gene combined with MFH had a good therapeutic effect on hepatoma, far better than any of the monotherapies; furthermore, no significant side effects were found . It might be an applicable strategy for hepatic cancer treatment. However, how did the combination therapy exert therapeutic effects on hepatoma? What was the mechanism? This was unclear.
The combined hepatoma-targeted therapy of radionuclide, suicide gene, and MFH linked organically by PEI-MZF-NPs presented an obvious complementary synergy. It had a good anticancer effect, far better than any involved monotherapy. Its mechanism may be involved in the downregulation of Ki67 expression leading to tumor cell proliferation repression and inhibition of survivin, bcl-2, p53, and livin protein expression inducing tumor cell apoptosis, negatively regulating VEGF protein expression, and reducing vascular endothelial cells resulting in tumor angiogenesis inhibition and microvascular density decreasing and inducing tumor cell necrosis. These findings offer a basic data support and theoretical foundation for the clinical application of the combination therapy.