RESUMEN
Fangchinoline (FAN), an alkaloid extracted from Stephania tetrandra, has a variety of biological and pharmacological activities, but evidence of its effects on colon adenocarcinoma (COAD) is limited. Therefore, the present study aimed to elucidate the molecular mechanisms by which FAN affects COAD. The cytotoxicity, viability and proliferation of DLD1 and LoVo cells were assessed in the presence of FAN using MTT and colony formation assays. The effects of FAN on apoptosis and the cell cycle in COAD cells were analysed by flow cytometry, and the migration and invasion of these cells were assessed by wound healing and Transwell experiments. Furthermore, a network pharmacological analysis was conducted to investigate the target of FAN and the results were confirmed by western blotting. In addition, a xenograft model was established in nude mice, and ultrasound imaging was used to assess the preclinical therapeutic effects of FAN in vivo. To the best of our knowledge, the results of this study provided the first evidence that FAN inhibited cellular proliferation, stemness, migration, invasion, angiogenesis and epithelialmesenchymal transition (EMT), and induced apoptosis and G1phase cell cycle arrest. Network pharmacological analysis further confirmed that FAN prevented EMT through the epidermal growth factor receptor (EGFR)phosphoinositide 3kinase (PI3K)/AKT signalling pathway. Finally, FAN significantly repressed tumour growth and promoted apoptosis in xenografts. Thus, targeting EGFR with FAN may offer a novel therapeutic approach for COAD.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Bencilisoquinolinas/farmacología , Neoplasias del Colon/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Adenocarcinoma/patología , Animales , Bencilisoquinolinas/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , Medicamentos Herbarios Chinos/uso terapéutico , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cyclovirobuxine D (CVBD) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVBD has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVBD on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVBD and further elucidate its molecular mechanism(s). DLD1 and LoVo cell lines were selected to evaluate the antitumor effect of CVBD. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVBDtreated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVBD in vivo. It was identified that CVBD inhibited the proliferation, migration, stemness, angiogenesis and epithelialmesenchymal transition of CRC cells, and induced apoptosis and Sphase arrest. In addition, CVBD significantly inhibited the growth of xenografts. It is notable that CVBD exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVBD exerted anticancer effects through the CTHRC1AKT/ERKSnail signaling pathway. Targeted therapy combining CTHRC1 with CVBD may offer a promising novel therapeutic approach for CRC treatment.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias del Colon/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Proteínas de la Matriz Extracelular/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/patología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinogénesis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Neoplasias del Colon/irrigación sanguínea , Neoplasias del Colon/patología , Medicamentos Herbarios Chinos/uso terapéutico , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/metabolismo , RNA-Seq , Factores de Transcripción de la Familia Snail/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: Regional chemotherapy using hepatic artery catheters is a good method of treating patients with colorectal cancer liver metastases. We investigated the survival of patients with liver metastases from colorectal cancer using 5-fluorouracil (5-FU) and mitomycin C Cthrough implantable hepatic arterial infusion port. METHODS: Seventy-five patients with inoperable liver metastases from colorectal cancer were included between March, 1992 and November, 2001. We placed implantable hepatic arterial catheter (HAC) port by laparotomy. 5-FU, 1 000 mg/ m(2)/d continuous infusion for five days every four weeks, was delivered in the hepatic arterial catheter through the port. Mitomycin C, 30 mg/m(2)/d infusion in the first day every cycle through the port. Response to the treatment was evaluated by serial determinations of plasma CEA and imaging techniques consisting of computerized tomography and sonography of liver. RESULTS: Sixty-eight were performed hepatic artery chemotherapy and fifty-six were followed up among seventy-five HAC patients. Twenty-six patients(46.4 %) have responded and 4 complete remission were achieved. Eight patients (14.3 %) had stable liver metastases. Twenty-two patients (39.3 %) were progressed with increased tumor size and number. Twenty-nine patients(51.8%) had a decreased serum CEA level, while 10 patients (17.9 %) were stable and 17 patients (30.4 %) had an increased serum CEA level. There were no operative death in this series. Complications, which occurred in 18 patients (32.1 %), were as followed: hepatic artery thrombosis in 11, Upper gastric and intestinal bleeding in 3, liver abscess in 1, pocket infection in 1, cholangitis in 1, and hepatic artery pseudo-aneurysm in one patient. CONCLUSION: Combined infusion of 5-FU and mitomycin C by hepatic artery catheter port is an effective treatment for liver metastases from colorectal cancer. The high response and lower complication rates prove the adjuvant treatment of colorectal cancer with this treatment.