ABSTRACT
Tumor metastasis is the leading cause of cancer death; due to the progress made in the elucidation of the mechanism of cancer cell metastasis, there is hope for patients with severe stages of cancer. Curcumin, as a novel anti-cancer drug, has been applied in cancer therapy; however, the toxicity of curcumin hinders its application. Herein, we constructed a novel derivative, WZ35, and evaluated its metastatic inhibition properties in vitro and in vivo. CCK-8 assay was performed to evaluate the tumor suppressive activity of WZ35. Cell apoptosis was detected by flow cytometry analysis. Transwell cell migration assay and RTCA were used to detect cell migration in mock and WZ35-treated cells. Western blotting was performed to analyze molecular alteration with different treatments. In this study, we found that curcumin and its derivative WZ35 could dramatically suppress proliferation, invasion, and migration of the hepatocellular HCCLM3, HepG2, and Huh7 cancer cells. Moreover, the cancer cell metastatic markers MMP-2, MMP-9, and N-cadherin were decreased, and E-cadherin was up-regulated. In addition, our data show that WZ35 promotes ROS-dependent JNK activation that is essential for WZ35-caused cell metastasis suppression. Moreover, the NAC and JNK inhibitor SP600125 could dramatically reverse WZ35-caused MMP-2, MMP-9, and N-cadherin reduction and E-cadherin up-regulation. We have also found that WZ35 exhibits powerful anti-metastasis activity of HCCLM3 in vivo. In conclusion, our data indicated that WZ35 could be a candidate for the treatment of metastatic liver cancer patients.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Curcumin/administration & dosage , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , MAP Kinase Kinase 4/pharmacology , Reactive Oxygen Species/metabolism , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/physiopathology , Cell Movement/drug effects , Curcumin/analogs & derivatives , Female , Humans , Liver Neoplasms/genetics , Liver Neoplasms/physiopathology , Mice , Mice, Inbred BALB C , Neoplasm MetastasisSubject(s)
Anthracenes/pharmacology , Hearing Loss/prevention & control , MAP Kinase Kinase 4/pharmacology , MAP Kinase Signaling System/drug effects , Tumor Necrosis Factor-alpha/pharmacology , Animals , Apoptosis/drug effects , Auditory Threshold/drug effects , Cells, Cultured , Disease Models, Animal , Electrodes, Implanted , Guinea Pigs , Hair Cells, Auditory/cytology , Hair Cells, Auditory/drug effects , In Vitro Techniques , Injections, Intralesional , Organ of Corti/cytology , Rats , Reference Values , Sensitivity and SpecificityABSTRACT
AIM: The excessive proliferation and migration of vascular smooth muscle cells (SMCs) and angiogenesis of endothelial cells (ECs) participate in the growth and instability of atherosclerotic plaques. It is unclear whether Jun N-terminal kinase (JNK) is pro-or anti-atherogenic. METHODS: We examined the direct effect of JNK inhibitor (JNK-I) on the proliferation and formation of tubes by human coronary SMCs and human coronary ECs. RESULTS: Culture medium from JNK-I-treated SMCs prevented ECs from forming tubes in an in vitro model of angiogenesis indirectly by reducing the amount of vascular endothelial growth factor (VEGF) released from SMCs. In addition, JNK-I attenuated the expression of pro-matrix metalloproteinase-2 in ECs. When added back to the medium of SMCs treated with JNK-I, VEGF blocked the inhibitory effect on the formation of tubes. CONCLUSION: Our results indicate JNK-I to have a direct anti-atherogenic effect in SMCs and ECs.
Subject(s)
Endothelial Cells/metabolism , MAP Kinase Kinase 4/antagonists & inhibitors , MAP Kinase Kinase 4/metabolism , Matrix Metalloproteinases, Secreted/metabolism , Muscle, Smooth, Vascular/metabolism , Neovascularization, Physiologic/drug effects , Vascular Endothelial Growth Factor A/metabolism , Atherosclerosis/metabolism , Atherosclerosis/pathology , Blotting, Western , Cell Culture Techniques , Cell Proliferation/drug effects , Coronary Vessels/pathology , Humans , MAP Kinase Kinase 4/pharmacology , Matrix Metalloproteinases, Secreted/drug effects , Muscle, Smooth, Vascular/pathology , Vascular Endothelial Growth Factor A/drug effectsABSTRACT
It has been demonstrated that the Phellinus linteus (PL) mushroom, which mainly consists of polysaccharides, possesses antitumour activity. The mechanisms of PL against malignant growth remain unknown. The anticancer drug doxorubicin (Dox) has been shown to induce apoptosis via initiating a caspase cascade. In this investigation, we tested the effect of PL on Dox-induced apoptosis in prostate cancer LNCaP cells. We showed that PL or Dox, at relatively low doses, does not induce apoptosis in the cells. However, combination treatment with low doses of PL and Dox results in a synergistic effect on the induction of apoptosis. In this apoptotic process, caspases 8, 3 and BID are cleaved, and the addition of caspase inhibitor z-VADfmk completely blocks apoptosis. In addition, JNK is activated in response to PL or the combination treatment in LNCaP cells. The suppression of JNK partially inhibits the induction of apoptosis elicited by the co-treatment. These findings indicate that PL has a synergistic effect with Dox to activate caspases in prostate cancer LNCaP cells. Our study also suggests that PL has therapeutic potential to augment the magnitude of apoptosis induced by antiprostate cancer drugs.
