The cytochrome P450 epoxygenase, CYP2J2, converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs). We found recently that this enzyme is dramatically up-regulated in a variety of established human carcinoma cell lines and in human cancerous tissue and promotes the neoplastic phenotype. In the present study, we tested the hypothesis that specific inhibitors of CYP2J2 related to the drug terfenadine are effective antitumor agents. Four of these inhibitors (compounds 4, 5, 11, and 26) were tested for effectiveness in vitro and in vivo. In Tca-8113 cells, the CYP2J2 inhibitors decreased EET production by approximately 60%, whereas they had no effect on CYP2J2 mRNA or protein expression. Compound 26 inhibited the proliferation of human tumor cells, reduced their ability to adhere, invade, and migrate, and attenuated activation of epithelial growth factor receptor signal and kinases and phosphatidylinositol 3 kinase/Akt pathways. Inhibition of CYP2J2 also significantly potentiated human tumor cell apoptosis and caused a corresponding increase in caspase-3 activity and change in expression of apoptosisrelated proteins Bax and Bcl-2. In murine xenograft models using MDA-MB-435 cells, treatment with compound 26 significantly repressed tumor growth, decreased lung metastasis, and was associated with increased expression of the anticancer genes CD82 and nm23, without causing toxicity. These data suggest that CYP2J2 inhibitors hold significant promise for use in treatment of neoplastic diseases.
This study suggests that IMRT results in milder hematological toxicity than either 3DCRT or RapidARC. Dosimetric parameters were associated with the incidence of HT in cervical cancer patients who received concurrent chemoradiotherapies.
Herbal medicines have been recognized as an attractive approach for cancer therapy with minimal side effects. The present study investigated the type of interaction between a novel lipid-soluble extract from Pinellia pedatisecta Schott (PE) and cisplatin (CDDP) on human cervical cancer SiHa and CaSki cell lines in vitro. The mechanism of this combination was studied using cell proliferation, invasion and apoptosis assays, and by analyzing cell cycle distribution and protein expression, with a focus on DNA damage response (DDR) activation. Equipotent combinations of PE and CDDP were determined by isobologram analysis, in order to evaluate potential synergy. The combination index for SiHa cells was 0.43, and the index for CaSki cells was 0.68, indicating synergy. Treatment with PE and CDDP combined resulted in a significantly greater inhibition of invasion in the two cells, compared with either drug alone (SiHa, P<0.01; CaSki, P<0.001). This co-treatment induced significantly more apoptosis in the two cell lines, and arrested cells at the G0/G1 phase and G2/M phase in SiHa and CaSki, respectively, with a significant decrease (P<0.01) in S phase cells in the two cell lines. Combined PE and CDDP targeting synergistically enhanced the expression of markers of DDR (phosphorylation of ataxia-telangiectasia mutated, checkpoint kinase (Chk)-1, Chk-2, and γ-H2A histone family member X) in cells. These results suggest that PE and cisplatin act synergistically in cervical cancer cells with high DDR activation. The approach presented in the present study may have important implications for the pharmacological mechanism of Pinellia pedatisecta Schott and cervical cancer therapeutic strategies.
Dimercaptosuccinic acid (DMSA) is an oral heavy metal chelator. Although DMSA is the most acceptable chelator in the urinary excretion of toxic elements from children and adults, its defects in plasma binding and the membrane permeability limit its interaction with intracellular elements and affect its efficacy in chelation therapy. Herein, a novel nanocomposite composed of mesoporous silica nanoparticles (MSNs), disulfide bond, and DMSA was synthesized and characterized with a scanning/transmission electron microscope, IR and Raman spectra, and TGA analysis. The in vitro interactions with glutathione (GSH) and cellular uptake assays showed that it was able to be stable in extracellular environments such as in blood, be internalized by cells, and release DMSA inside via GSH-triggered disulfide cleavage reaction. The in vitro adsorption assays showed that MSNs-SH as its intracellular metabolite had strong adsorbability for models of Hg2+ or Pb2+. The hemolysis and cell viability assays showed that it was compatible with blood and cells even at a concentration of 1000 μg·mL−1. All above could not only enable it to be a GSH-responsive drug delivery system (DDS) for DMSA delivery but also to be a solution for its defects and efficacy. Thus, introduction of intelligent DDS might open a new avenue for DMSA-based chelation therapy.
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