RESUMEN
Melanoma is a highly metastatic cancer with a low incidence rate, but a high mortality rate. Patchouli alcohol (PA), a tricyclic sesquiterpene, is considered the main active component in Pogostemon cablin Benth, which improves wound healing and has anti-tumorigenic activity. However, the pharmacological action of PA on anti-melanoma remains unclear. Thus, the present study aimed to investigate the role of PA in the proliferation, cell cycle, apoptosis and migration of melanoma cells. These results indicated that PA selectively inhibited the proliferation of B16F10 cells in a dose- and time-dependent manner. It induced cell cycle arrest at the G0 /G1 phase and typical morphological changes in apoptosis, such as chromatin condensation, DNA fragmentation and apoptotic bodies. In addition, PA reduced the migratory ability of B16F10 cells by upregulating E-cadherin and downregulating p-Smad2/3, vimentin, MMP-2 and MMP-9 expression. PA was also found to strongly suppress tumour growth in vivo. Furthermore, PA combined with cisplatin synergistically inhibited colony formation and migration of B16F10 cells and attenuated the development of resistance to treatment. Therefore, the results of this study indicate that PA may play a pivotal role in inducing apoptosis and reducing the migration of melanoma cells, and may thus be a potential candidate for melanoma treatment.
Asunto(s)
Melanoma , Sesquiterpenos , Humanos , Cisplatino/farmacología , Sesquiterpenos/farmacología , Línea Celular Tumoral , Apoptosis , Proliferación CelularRESUMEN
Glioblastoma (GB) is one of the most aggressive and malignant tumors of the central nervous system. Conventional treatment for GB requires surgical resection followed by radiotherapy combined with temozolomide chemotherapy; however, the median survival time is only 12-15 months. Angelica sinensis Radix (AS) is commonly used as a traditional medicinal herb or a food/dietary supplement in Asia, Europe, and North America. This study aimed to investigate the effect of AS-acetone extract (AS-A) on the progression of GB and the potential mechanisms underlying its effects. The results indicated that AS-A used in this study showed potency in growth inhibition of GB cells and reduction of telomerase activity. In addition, AS-A blocked the cell cycle at the G0/G1 phase by regulating the expression of p53 and p16. Furthermore, apoptotic morphology, such as chromatin condensation, DNA fragmentation, and apoptotic bodies, was observed in AS-A-treated cells, induced by the activation of the mitochondria-mediated pathway. In an animal study, AS-A reduced tumor volume and prolonged lifespans of mice, with no significant changes in body weight or obvious organ toxicity. This study confirmed the anticancer effects of AS-A by inhibiting cell proliferation, reducing telomerase activity, altering cell cycle progression, and inducing apoptosis. These findings suggest that AS-A has great potential for development as a novel agent or dietary supplement against GB.
Asunto(s)
Glioblastoma , Telomerasa , Humanos , Ratones , Animales , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Telomerasa/metabolismo , Telomerasa/farmacología , Telomerasa/uso terapéutico , Apoptosis , Puntos de Control del Ciclo Celular , Ciclo Celular , Proliferación Celular , Telómero/metabolismo , Telómero/patología , Mitocondrias , Línea Celular TumoralRESUMEN
Background: Cedrol is a natural sesquiterpene alcohol found in Cedrus atlantica, which has been proven to have a broad spectrum of biological activities, such as antimicrobial, anti-inflammatory, analgesic, anxiolytic, and anti-cancer effects. However, the underlying anticancer mechanisms and in vivo inhibitory effects of cedrol on colorectal cancer (CRC) have not been elucidated. In the present study, we investigated the anti-CRC potential of cedrol using in vitro and in vivo models. Methods: The effects of cedrol on cell viability, cell cycle progression, and apoptosis of HT-29 and CT-26 cells were detected by MTT, flow cytometry, and TUNEL assays. Western blotting was used to measure protein expression for molecular signaling analyses. Results: Cedrol inhibited HT-29 and CT-26 cell proliferation in a time- and dose-dependent manner, with IC50 values of 138.91 and 92.46 µM, respectively. Furthermore, cedrol induced cell cycle arrest at the G0/G1 phase by regulating the expression of cell cycle regulators, such as CDK4 and cyclin D1, and triggered apoptosis through extrinsic (FasL/caspase-8) and intrinsic (Bax/caspase-9) pathways. In addition, cedrol in combination with the clinical drug 5-fluorouracil exhibited synergistic inhibitory effects on CRC cell growth. Importantly, cedrol treatment suppressed the progression of CRC and improved the survival rate of animals at a well-tolerated dose. Conclusion: These results suggest that cedrol has an anti-cancer potential via induction of cell cycle arrest and apoptosis, and it could be considered as an effective agent for CRC therapy.
Asunto(s)
Caspasas , Neoplasias Colorrectales , Animales , Puntos de Control del Ciclo Celular , Apoptosis , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismoRESUMEN
Kynurenine 3-monooxygenase (KMO) is the pivotal enzyme in the kynurenine pathway and is located on the mitochondrial outer membrane. The dysregulation of KMO leads to various neurodegenerative diseases; however, it is rarely mentioned in cancer progression. Our previous study showed that KMO overexpression in canine mammary gland tumors (cMGT) is associated with poor prognosis in cMGT patients. Surprisingly, it was also found that KMO can be located on the cell membranes of cMGT cells, unlike its location in normal cells, where KMO is expressed only within the cytosol. Since cMGT and human breast cancer share similar morphologies and pathogenesis, this study investigated the possibility of detecting surface KMO in human breast cancers and the role of surface KMO in tumorigenesis. Using immunohistochemistry (IHC), flow cytometry (FC), immunofluorescence assay (IFA), and transmission electron microscopy (TEM), we demonstrated that KMO can be aberrantly and highly expressed on the cell membranes of breast cancer tissues and in an array of cell lines. Masking surface KMO with anti-KMO antibody reduced the cell viability and inhibited the migration and invasion of the triple-negative breast cancer cell line, MDA-MB-231. These results indicated that aberrant surface expression of KMO may be a potential therapeutic target for human breast cancers.
Asunto(s)
Quinurenina 3-Monooxigenasa/biosíntesis , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/secundario , Proliferación Celular , Humanos , Quinurenina 3-Monooxigenasa/análisis , Neoplasias de la Mama Triple Negativas/química , Neoplasias de la Mama Triple Negativas/patología , Células Tumorales CultivadasRESUMEN
Breast cancer is the second most common malignancy in women. Current clinical therapy for breast cancer has many disadvantages, including metastasis, recurrence, and poor quality of life. Furthermore, it is necessary to find a new therapeutic drug for breast cancer patients to meet clinical demand. n-Butylidenephthalide (BP) is a natural and hydrophobic compound that can inhibit several tumors. However, BP is unstable in aqueous or protein-rich environments, which reduces the activity of BP. Therefore, we used an LPPC (Lipo-PEG-PEI complex) that can encapsulate both hydrophobic and hydrophilic compounds to improve the limitation of BP. The purpose of this study is to investigate the anti-tumor mechanisms of BP and BP/LPPC and further test the efficacy of BP encapsulated by LPPC on SK-BR-3 cells. BP inhibited breast cancer cell growth, and LPPC encapsulation (BP/LPPC complex) enhanced the cytotoxicity on breast cancer by stabilizing the BP activity and offering endocytic pathways. Additionally, BP and LPPC-encapsulated BP induced cell cycle arrest at the G0/G1 phase and might trigger both extrinsic as well as intrinsic cell apoptosis pathway, resulting in cell death. Moreover, the BP/LPPC complex had a synergistic effect with doxorubicin of enhancing the inhibitory effect on breast cancer cells. Consequently, LPPC-encapsulated BP could improve the anti-cancer effects on breast cancer in vitro. In conclusion, BP exhibited an anti-cancer effect on breast cancer cells, and LPPC encapsulation efficiently improved the cytotoxicity of BP via an acceleration of entrapment efficiency to induce cell cycle block and apoptosis. Furthermore, BP/LPPC exhibited a synergistic effect in combination with doxorubicin.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Anhídridos Ftálicos/administración & dosificación , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Combinación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Liposomas , Nanopartículas/química , Anhídridos Ftálicos/farmacocinética , Polietilenglicoles/química , Polietileneimina/análogos & derivados , Polietileneimina/químicaRESUMEN
Juniperus indica Bertol. is an herbal plant that belongs to the genus Juniperus, which is commonly used in traditional medicine to refresh the mind and for diuretic use. However, few studies have reported the function of J. indica Bertol. Hence, this study aimed to investigate the anti-tumor and synergistic potential of J. indica Bertol. extract (JIB extract) for melanoma cells. Our results indicated the anti-melanoma activity of JIB extract. JIB extract induced cell cycle arrest at the G0/G1 phase and decreased cyclin and cdk protein expressions. In addition, AKT/mTOR signaling and MAPK signaling were inhibited by JIB extract to suppress melanoma cell growth and proliferation. Additionally, JIB extract induced B16/F10 cell apoptosis via the caspase cascade. According to the JIB extract's anti-melanoma capacity, to assess the synergistic effects of cisplatin and JIB extract. The results demonstrated that JIB extract combined with cisplatin enhanced the inhibition of cell growth, proliferation, and survival through the obstruction of cell cycle progression and AKT/mTOR and MAPK signaling as well as the induction of cell apoptosis. Collectively, our results indicate that JIB extract showed anti-tumor effects and synergized with cisplatin against B16/F10 cells, indicating the possibility of JIB extract to be developed as adjuvant therapy for melanoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Juniperus/química , Melanoma/tratamiento farmacológico , Extractos Vegetales/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/uso terapéutico , Perros , Sinergismo Farmacológico , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células de Riñón Canino Madin Darby , Melanoma/patología , Ratones , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Glioblastoma (GBM) is the most common malignant primary brain tumor in humans, exhibiting highly infiltrative growth and drug resistance to conventional chemotherapy. Cedrus atlantica (CAt) extract has been shown to decrease postoperative pain and inhibit the growth of K562 leukemia cells. The aim of this study was to assess the anti-GBM activity and molecular mechanism of CAt extract in vitro and in vivo. The results showed that CAt extract greatly suppressed GBM cells both in vitro and in vivo and enhanced the survival rate in subcutaneous and orthotopic animal models. Moreover, CAt extract increased the level of ROS and induced DNA damage, resulting in cell cycle arrest at the G0/G1 phase and cell apoptosis. Western blotting results indicated that CAt extract regulates p53/p21 and CDK4/cyclin D1 protein expression and activates extrinsic and intrinsic apoptosis. Furthermore, CAt extract enhanced the cytotoxicity of Temozolomide and decreased AKT/mTOR signaling by combination treatment. In toxicity assays, CAt extract exhibited low cytotoxicity toward normal cells or organs in vitro and in vivo. CAt extract suppresses the growth of GBM by induction of genotoxicity and activation of apoptosis. The results of this study suggest that CAt extract can be developed as a therapeutic agent or adjuvant for GBM treatment in the future.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Cedrus/química , Glioblastoma/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Glioblastoma/patología , Humanos , Ratones , Extractos Vegetales/uso terapéutico , Ratas , Temozolomida/farmacología , Temozolomida/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This study investigated the anti-leukemic effects of Cedrus atlantica extract (CAt extract) on cell cycle distribution and apoptosis in human acute myeloid leukemia (AML) cells. AML often occurs in older adults, accounting for 60% of the cases, and is likely to be resistant to chemotherapy due to multidrug resistance, resulting in early death during cancer treatment. With the increasing focus on prevention medicine, natural plant components are being used as a major source for the development of therapeutic drugs or functional foods to cure or alleviate the disease. Cedrus species are known to have anti-inflammatory, antimicrobial, antiviral, and anticancer effects; however, the anticancer effects of CAt extract have not been elucidated. In this study, CAt extract demonstrated an inhibitory effect on human leukemia cells in a concentration-dependent manner; CAt extract induced G0/G1 phase arrest via restrained protein levels of p-Rb and cell cycle-related proteins. After CAt extract exposure, the extrinsic and intrinsic apoptotic pathways were activated through caspase-8, -9, and -3 cleavage. Additionally, CAt extract suppressed VEGF, MMP-2, and MMP-9 expression. This study demonstrated that CAt extract treatment significantly reduced cell growth, cell cycle arrest in the G0/G1 phase, and induction of apoptosis, leading to leukemia cell death.
Asunto(s)
Apoptosis/efectos de los fármacos , Cedrus/química , Ciclo Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Enfermedad Aguda , Animales , Caspasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células HL-60 , Humanos , Células Jurkat , Células K562 , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Células RAW 264.7 , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Glioblastoma (GBM) is a common and aggressive brain tumor with a median survival of 12-15 months. Temozolomide (TMZ) is a first-line chemotherapeutic agent used in GBM therapy, but the occurrence of drug resistance limits its antitumor activity. The natural compound cedrol has remarkable antitumor activity and is derived from Cedrus atlantica. In this study, we investigated the combined effect of TMZ and cedrol in GBM cells in vitro and in vivo. The TMZ and cedrol combination treatment resulted in consistently higher suppression of cell proliferation via regulation of the AKT and MAPK signaling pathways in GBM cells. The combination treatment induced cell cycle arrest, cell apoptosis, and DNA damage better than either drug alone. Furthermore, cedrol reduced the expression of proteins associated with drug resistance, including O6-methlyguanine-DNA-methyltransferase (MGMT), multidrug resistance protein 1 (MDR1), and CD133 in TMZ-treated GBM cells. In the animal study, the combination treatment significantly suppressed tumor growth through the induction of cell apoptosis and decreased TMZ drug resistance. Moreover, cedrol-treated mice exhibited no significant differences in body weight and improved TMZ-induced liver damage. These results imply that cedrol may be a potential novel agent for combination treatment with TMZ for GBM therapy that deserves further investigation.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Antineoplásicos Fitogénicos/farmacología , Daño del ADN , Metilasas de Modificación del ADN/biosíntesis , Enzimas Reparadoras del ADN/biosíntesis , Resistencia a Antineoplásicos/efectos de los fármacos , Sesquiterpenos Policíclicos/farmacología , Temozolomida/farmacología , Proteínas Supresoras de Tumor/biosíntesis , Animales , Antineoplásicos Alquilantes/toxicidad , Apoptosis/efectos de los fármacos , Cedrus/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Sinergismo Farmacológico , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Estructura Molecular , Proteína Oncogénica v-akt/efectos de los fármacos , Temozolomida/toxicidad , Proteínas Supresoras de Tumor/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The anti-angiogenic fusion protein RBDV-IgG1 Fc (RBDV), which comprises the receptor-binding domain of vascular endothelial growth factor-A (VEGF-A), has shown antitumour effects by reducing angiogenesis in vivo. This study used the cationic lipoplex lipo-PEG-PEI-complex (LPPC) to simultaneously encapsulate both the RBDV targeting protein and the RBDV plasmid (pRBDV) without covalent bonds to assess VEGFR targeting gene therapy in mice with melanoma in vivo. RESULTS: LPPC protected the therapeutic transgene from degradation by DNase, and the LPPC/RBDV complexes could specifically target VEGFR-positive B16-F10 cells both in vitro and in vivo. With or without RBDV protein-targeting direction, the pRBDV-expressing RBDV proteins were expressed and reached a maximal concentration on the 7th day in the sera after transfection in vivo and significantly elicited growth suppression against B16-F10 melanoma but not IgG1 control proteins. In particular, LPPC/pRBDV/RBDV treatment with the targeting molecules dramatically inhibited B16-F10 tumour growth in vivo to provide better therapeutic efficacy than the treatments with gene therapy with IgG1 protein targeting or administration of a protein drug with RBDV. CONCLUSIONS: The simultaneous combination of the LPPC complex with pRBDV gene therapy and RBDV protein targeting might be a potential tool to conveniently administer targeted gene therapy for cancer therapy.
Asunto(s)
Inhibidores de la Angiogénesis/genética , Terapia Genética/métodos , Liposomas/química , Melanoma Experimental/terapia , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Células 3T3 , Animales , Línea Celular Tumoral , Proliferación Celular , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/metabolismo , Masculino , Melanoma Experimental/mortalidad , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Plásmidos/química , Plásmidos/genética , Plásmidos/uso terapéutico , Dominios Proteicos/genética , Receptores de Factores de Crecimiento Endotelial Vascular/genética , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/aislamiento & purificación , Tasa de Supervivencia , Trasplante Homólogo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The purpose of the study was to elucidate the anti-hepatoma effects and mechanisms of Pogostemon cablin essential oils (PPa extract) in vitro and in vivo. PPa extract exhibited an inhibitory effect on hepatocellular carcinoma (HCC) cells and was less cytotoxic to normal cells, especially normal liver cells, than it was to HCC cells, exerting a good selective index. Additionally, PPa extract inhibited HCC cell growth by blocking the cell cycle at the G0/G1 phase via p53 dependent or independent pathway to down regulated cell cycle regulators. Moreover, PPa extract induced the FAS-FASL-caspase-8 system to activate the extrinsic apoptosis pathway, and it increased the bax/bcl-2 ratio and reduced ΔΨm to activate the intrinsic apoptosis pathway that might be due to lots of reactive oxygen species (ROS) production which was induced by PPa extract. In addition, PPa extract presented to the potential to act synergistically with sorafenib to effectively inhibit HCC cell proliferation through the Akt/mTOR pathway and reduce regrowth of HCC cells. In an animal model, PPa extract suppressed HCC tumor growth and prolonged lifespan by reducing the VEGF/VEGFR axis and inducing tumor cell apoptosis in vivo. Ultimately, PPa extract demonstrated nearly no or low system-wide, physiological, or pathological toxicity in vivo. In conclusion, PPa extract effectively inhibited HCC cell growth through inducing cell cycle arrest and activating apoptosis in vitro and in vivo. Furthermore, PPa extract exhibits less toxicity toward normal cells and organs than it does toward HCC cells, which might lead to fewer side effects in clinical applications. PPa extract may be developed into a clinical drug to suppress tumor growth or functional food to prevent HCC initiation or chemoprotection of HCC recurrence.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Daño del ADN , Extractos Vegetales/farmacología , Pogostemon/química , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/química , Apoptosis , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Femenino , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Oral cancer-a type of head and neck cancer-is estimated to be the fifth most common cancer in Taiwan. However, efficacious therapies for oral cancer are still lacking due to drug resistance and recurrence. Consequently, the identification of new anticancer agents for clinical treatment is needed. Juniperus indica Bertol is a plant of the Juniperus genus often used as a treatment in traditional medicine due to its anti-inflammatory, antibacterial and diuretic functions. The biofunctions of Juniperus indica Bertol including its anticancer potential, have not been fully explored. As a result, the aim of this research was to investigate the anticancer activity of Juniperus indica Bertol extract (JIB extract) and determine whether JIB extract has synergistic effects with cisplatin in oral cancer. These results are the first to demonstrate that JIB extract exhibits anticancer capacity and synergizes with cisplatin to treat oral cancer. Our findings indicate that JIB extract has a potential to develop anticancer agent and chemo therapeutic adjuvant for oral cancer.
Asunto(s)
Antineoplásicos Fitogénicos , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Cisplatino , Juniperus/química , Neoplasias de la Boca , Proteínas de Neoplasias/metabolismo , Extractos Vegetales , Animales , Antineoplásicos Fitogénicos/agonistas , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Cisplatino/agonistas , Cisplatino/farmacología , Perros , Sinergismo Farmacológico , Activación Enzimática/efectos de los fármacos , Humanos , Células de Riñón Canino Madin Darby , Ratones , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/patología , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
Colorectal cancer (CRC) is the third most common type of cancer and the second most common cause of cancer-related death in the world. N-Butylidenephthalide (BP), a natural compound, inhibits several cancers, such as hepatoma, brain tumor and colon cancer. However, due to the unstable structure, the activity of BP is quickly lost after dissolution in an aqueous solution. A polycationic liposomal polyethylenimine and polyethylene glycol complex (LPPC), a new drug carrier, encapsulates both hydrophobic and hydrophilic compounds, maintains the activity of the compound, and increases uptake of cancer cells. The purpose of this study is to investigate the antitumor effects and protection of BP encapsulated in LPPC in CRC cells. The LPPC encapsulation protected BP activity, increased the cytotoxicity of BP and enhanced cell uptake through clathrin-mediated endocytosis. Moreover, the BP/LPPC-regulated the expression of the p21 protein and cell cycle-related proteins (CDK4, Cyclin B1 and Cyclin D1), resulting in an increase in the population of cells in the G0/G1 and subG1 phases. BP/LPPC induced cell apoptosis by activating the extrinsic (Fas, Fas-L and Caspase-8) and intrinsic (Bax and Caspase-9) apoptosis pathways. Additionally, BP/LPPC combined with 5-FU synergistically inhibited the growth of HT-29 cells. In conclusion, LPPC enhanced the antitumor activity and cellular uptake of BP, and the BP/LPPC complex induced cell cycle arrest and apoptosis, thereby causing death. These findings suggest the putative use of BP/LPPC as an adjuvant cytotoxic agent for colorectal cancer.
Asunto(s)
Antineoplásicos/química , Neoplasias Colorrectales/tratamiento farmacológico , Liposomas/química , Anhídridos Ftálicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Células HT29 , Humanos , Liposomas/farmacología , Anhídridos Ftálicos/farmacologíaRESUMEN
Cedrus atlantica is widely used in herbal medicine. However, the anti-cancer activity of C. atlantica extract (CAt extract) has not been clarified in hepatocellular carcinoma. In the study, we elucidated the anti-hepatoma capacity of CAt extract on HCC in vitro and in vivo. To explore the anti-hepatoma mechanisms of the CAt extract in vitro, HCC and normal cells were treated with the CAt extract, which showed marked inhibitory effects on HCC cells in a dose-dependent manner; in contrast, the CAt extract treatment was less cytotoxic to normal cells. In addition, our results indicate that the CAt extract induced apoptosis via caspase-dependent and independent apoptosis pathways. Furthermore, the CAt extract inhibited HCC tumor cell growth by restraining cell cycle progression, and it reduced the signaling of the AKT, ERK1/2, and p38 pathways. In the xenograft model, the CAt extract suppressed HCC tumor cell growth and prolonged lifespan by inhibiting PCNA protein expression, repressing part of the VEGF-induced autocrine pathway, and triggering strong expression of cleaved caspase-3, which contributed to cell apoptosis. Moreover, the CAt extract did not induce any obvious changes in pathological morphology or body weight, suggesting it had no toxicity. CAt extract exerted anti-tumor effects on HCC in vitro and in vivo. Thus, CAt extract could be used as a potential anti-cancer therapeutic agent against HCC.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Cedrus/química , Neoplasias Hepáticas/tratamiento farmacológico , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Carcinoma Hepatocelular/metabolismo , Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Citometría de Flujo , Cromatografía de Gases y Espectrometría de Masas , Células Hep G2 , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BACKGROUND: A cationic liposome-PEG-PEI complex (LPPC) was employed as a carrier for achieving targeted delivery of drug to human epidermal growth factor receptor-2 (HER2/neu)-expressing breast cancer cells. LPPC can be easily loaded with an anti-tumor drug and non-covalently associated with an anti-tumor antibody such as Herceptin that is clinically used to rapidly form immunoparticles within 1 h. RESULTS: Drug-loaded LPPC have an average size about 250 nm and a zeta potential of about 40 mV. Herceptin was complexed onto surface of the LPPC to form the drug/LPPC/Herceptin complexes. The size of curcumin/LPPC/Herceptin complexes were 280 nm and the zeta potentials were about 23 mV. Targeting ability of this delivery system was demonstrated through specific binding on surface of cells and IVIS images in vivo, which showed specific binding in HER2-positive SKBR3 cells as compared to HER2-negative Hs578T cells. Only the drug/LPPC/Herceptin complexes displayed dramatically increased the cytotoxic activity in cancer cells. Both in vitro and in vivo results indicated that Herceptin adsorbed on LPPC directed the immunocomplex towards HER2/neu-positive cells but not HER2/neu-negative cells. The complexes with either component (curcumin or doxorubicin) used in the LPPC-delivery system provided a better therapeutic efficacy compared to the drug treatment alone and other treatment groups, including clinical dosages of Herceptin and LipoDox, in a xenografted model. CONCLUSIONS: LPPC displays important clinical implications by easily introducing a specific targeting characteristic to drugs utilized for breast cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Polietilenglicoles/química , Polietileneimina/análogos & derivados , Receptor ErbB-2/metabolismo , Trastuzumab/administración & dosificación , Animales , Antineoplásicos/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Curcumina/administración & dosificación , Doxorrubicina/administración & dosificación , Liberación de Fármacos , Femenino , Xenoinjertos , Humanos , Liposomas , Células MCF-7 , Ratones Endogámicos BALB C , Tamaño de la Partícula , Polietileneimina/química , Propiedades de Superficie , Trastuzumab/inmunologíaRESUMEN
Cancer progression is associated with the development of antitumor autoantibodies in patients' sera. Although passive treatment with antitumor antibodies has exhibited remarkable therapeutic efficacy, inhibitory effects on tumor progression by endogenous antitumor autoantibodies (EAAs) have been limited. In this study, we show that P4N, a derivative of the plant lignan nordihydroguaiaretic acid (NDGA), enhanced the production of EAAs and inhibited tumor growth at low noncytotoxic concentrations via its immunoregulatory activity. Intratumoral injection of P4N improved the quantity and quality of EAAs, and passive transfer of P4N-induced EAAs dramatically suppressed lung metastasis formation and prolonged the survival of mice inoculated with metastatic CT26 tumor cells. P4N-induced EAAs specifically recognized two surface antigens, 78-kDa glucose-regulated protein (GRP78) and F1F0 ATP synthase, on the plasma membrane of cancer cells. Additionally, P4N treatment led to B-cell proliferation, differentiation to plasma cells, and high titers of autoantibody production. By serial induction of autocrine and paracrine signals in monocytes, P4N increased B-cell proliferation and antibody production via the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway. This mechanism provides a useful platform for studying and seeking a novel immunomodulator that can be applied in targeting therapy by improving the quantity and quality of the EAAs.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Factores Inmunológicos/administración & dosificación , Éteres Fenílicos/administración & dosificación , Piperidinas/administración & dosificación , Transducción de Señal , Activinas/genética , Activinas/metabolismo , Animales , Anticuerpos Antineoplásicos/sangre , Autoanticuerpos/sangre , Factor Activador de Células B/genética , Factor Activador de Células B/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Chaperón BiP del Retículo Endoplásmico , Epóxido Hidrolasas/genética , Epóxido Hidrolasas/metabolismo , Femenino , Expresión Génica , Inmunidad Humoral/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Carga TumoralRESUMEN
BACKGROUND/AIMS: Herbal materials derived from Juniperus communis (JCo) possess anticancer activity. In this study, we evaluated the efficacy of a JCo berry extract in suppressing glioblastoma growth. METHODS: The effects of JCo extract on the viability of normal and glioma cell lines was analyzed using a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The synergistic therapeutic effect of JCo extract and temozolomide (TMZ) on glioma cells was examined by MTT analysis. Flow cytometry analysis, the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) test, and western blotting were performed to identify the apoptotic pathway. To determine the in vivo efficacy of the JCo extract, rats were injected with 5 × 104 rat glioma RG2 cells in the back skin and brain hemisphere and then received a subcutaneous injection in the back skin that contained either JCo extract or vehicle. Finally, blood and histologic examinations were performed to evaluate JCo toxicity. RESULTS: The IC50 values of JCo extract were 57-69 µg/mL and 49-67 µg/mL in the glioblastoma cell lines after 24 and 48 h, respectively. However, in non-tumor cell lines, the respective IC50 values of JCo extract were 76-105 µg/mL and 77-108 µg/mL. The JCo extract had a stronger cytotoxicity and a larger range of IC50 values in glioma than in normal cells as compared to those effects caused by temozolomide (TMZ). In addition, the results of flow cytometry analysis, TUNEL test, and western blotting revealed that the JCo extract induced glioma cell cycle arrest through intrinsic and extrinsic apoptotic pathways. In the in vivo studies, a significant reduction of tumor size in JCo-treated rats, as measured by animal MRI, demonstrated that the JCo extract effectively inhibited glioma cell growth and successfully penetrated the blood-brain barrier. The immunohistochemical (IHC) staining detected positive signals of PCNA, VEGFR-1, and VEGFR -2 in 44.49%, 5.88%, and 5.85% of JCo-treated glioma cells, respectively. However, positive signals of PCNA, VEGFR-1, and VEGFR-2 were detected in 73.08%, 9.67%, and 11.70% of vehicle-treated glioma cells, respectively. The IHC examination of PCNA and VEGFR-1 and -2 indicated that JCo extract significantly decreased the degree of neovascularization. However, no significant differences in serum levels of blood cell count and hepatic enzymes, renal function index, and the histologic appearance of vital organs were detected between the JCo and vehicle-treated rats. CONCLUSION: The JCo extract penetrated the blood-brain barrier and significantly induced glioma cell apoptosis by reducing neovascularization via suppression of the PI3K/AKT/mTOR pathway. Furthermore, JCo extract was less cytotoxic to non-neoplastic vital organs than TMZ.
Asunto(s)
Apoptosis/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Juniperus/química , Extractos Vegetales/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Caspasa 3/química , Caspasa 3/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Sinergismo Farmacológico , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Juniperus/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Antígeno Nuclear de Célula en Proliferación/metabolismo , Temozolomida , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Gene therapy is a potent method to increase the therapeutic efficacy against cancer. However, a gene that is specifically expressed in the tumor area has not been identified. In addition, nonspecific expression of therapeutic genes in normal tissues may cause side effects that can harm the patients' health. Certain promoters have been reported to drive therapeutic gene expression specifically in cancer cells; however, low expression levels of the target gene are a problem for providing good therapeutic efficacy. Therefore, a specific and highly expressive promoter is needed for cancer gene therapy. METHODS: Bioinformatics approaches were utilized to analyze transcription factors (TFs) from high-throughput data. Reverse transcription polymerase chain reaction, western blotting and cell transfection were applied for the measurement of mRNA, protein expression and activity. C57BL/6JNarl mice were injected with pD5-hrGFP to evaluate the expression of TFs. RESULTS: We analyzed bioinformatics data and identified three TFs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), cyclic AMP response element binding protein (CREB), and hypoxia-inducible factor-1α (HIF-1α), that are highly active in tumor cells. Here, we constructed a novel mini-promoter, D5, that is composed of the binding sites of the three TFs. The results show that the D5 promoter specifically drives therapeutic gene expression in tumor tissues and that the strength of the D5 promoter is directly proportional to tumor size. CONCLUSIONS: Our results show that bioinformatics may be a good tool for the selection of appropriate TFs and for the design of specific mini-promoters to improve cancer gene therapy.
Asunto(s)
Biología Computacional , Regulación Neoplásica de la Expresión Génica , Vectores Genéticos/genética , Neoplasias/genética , Regiones Promotoras Genéticas , Animales , Línea Celular Tumoral , Biología Computacional/métodos , Expresión Génica , Perfilación de la Expresión Génica , Genes Reporteros , Humanos , Ratones , Ratones Transgénicos , Neoplasias/metabolismo , Unión Proteica , Mapeo de Interacción de Proteínas , Factores de Transcripción/metabolismo , TransgenesRESUMEN
Advanced melanoma can metastasize to distal organs from the skin and yield an aggressive disease and poor prognosis even after treatment with chemotherapeutic agents. The compound n-Butylidenephthalide (BP) is isolated from Angelica sinensis, which is used to treat anemia and gynecological dysfunction in traditional Chinese medicine. Studies have indicated that BP can inhibit cancers, including brain, lung, prostate, liver, and colon cancers. However, because BP is a natural hydrophobic compound, it is quickly metabolized by the liver within 24 h, and thus has limited potential for development in cancer therapy. This study investigated the anticancer mechanisms of BP through encapsulation with a novel polycationic liposome containing polyethylenimine (PEI) and polyethylene glycol complex (LPPC) in melanoma cells. The results demonstrated that BP/LPPC had higher cytotoxicity than BP alone and induced cell cycle arrest at the G0/G1 phase in B16/F10 melanoma cells. The BP/LPPC-treated cell indicated an increase in subG1 percentage and TUNEL positive apoptotic morphology through induction of extrinsic and intrinsic apoptosis pathways. The combination of BP and LPPC and clinical drug 5-Fluorouracil had a greater synergistic inhibition effect than did a single drug. Moreover, LPPC encapsulation improved the uptake of BP values through enhancement of cell endocytosis and maintained BP cytotoxicity activity within 24 h. In conclusion, BP/LPPC can inhibit growth of melanoma cells and induce cell arrest and apoptosis, indicating that BP/LPPC has great potential for development of melanoma therapy agents.
Asunto(s)
Antineoplásicos/administración & dosificación , Liposomas , Melanoma , Anhídridos Ftálicos/administración & dosificación , Poliaminas , Angelica sinensis/química , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/química , Humanos , Liposomas/química , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Ratones , Anhídridos Ftálicos/química , Anhídridos Ftálicos/aislamiento & purificación , Polielectrolitos , Polietilenglicoles/química , Polietileneimina/químicaRESUMEN
BACKGROUND: Tamoxifen is currently used for the treatment of both early and advanced estrogen receptor (ER) positive breast cancer in pre- and post-menopausal women. However, using tamoxifen routinely to inhibit endogenous or exogenous estrogen effects is occasionally difficult because of its potential side effects. OBJECTIVES: The aim of this study is to design a local drug delivery system to encapsulate tamoxifen for observing their efficacy of skin penetration, drug accumulation and cancer therapy. METHODS: A cationic liposome-PEG-PEI complex (LPPC) was used as a carrier for the encapsulation of tamoxifen and forming 'LPPC/TAM' for transdermal release. The cytotoxicity of LPPC/TAM was analyzed by MTT. The skin penetration, tumor growth inhibition and organ damages were measured in xenograft mice following transdermal treatment. RESULTS: LPPC/TAM had an average size less than 270 nm and a zeta-potential of approximately 40 mV. LPPC/TAM displayed dramatically increased the cytotoxic activity in all breast cancer cells, especially in ER-positive breast cancer cells. In vivo, LPPC drug delivery helped the fluorescent dye penetrating across the skim and accumulating rapidly in tumor area. Administration of LPPC/TAM by transdermal route inhibited about 86 % of tumor growth in mice bearing BT474 tumors. This local treatment of LPPC/TAM did not injury skin and any organs. CONCLUSION: LPPC-delivery system provided a better skin penetration and drug accumulation and therapeutic efficacy. Therefore, LPPC/TAM drug delivery maybe a useful transdermal tool of drugs utilization for breast cancer therapy.