RESUMO
Triple-negative breast cancer (TNBC) is highly aggressive, resulting in poor prognosis. Chemotherapy of TNBC relies on anti-cancer agents with strong cytotoxicity, but it causes several side effects with recurrence. While combinational approaches of chemotherapeutics have been highlighted as a new treatment strategy for TNBC to reduce side effects, combinations of anti-cancer agents with herbal medicines have not been reported. We recently reported that newly modified traditional Chinese medicine named SH003 inhibited TNBC growth. Considering a combinational strategy for TNBC treatment, we further studied synergistic effects of SH003 with various anti-cancer drugs in TNBC treatment. Here, we demonstrate that SH003 shows a synergistic effect with doxorubicin on TNBC treatment. Our in vitro cell viability assays revealed that SH003 and doxorubicin showed a synergistic effect in the well-defined TNBC cell line, MDA-MB-231. Moreover, we found that the combinational treatment caused Caspase-dependent apoptotic cell death. Our in vivo mouse xenograft tumor growth assays confirmed that combinational treatment of SH003 with doxorubicin repressed MDA-MB-231 tumor growth with no weight loss. Therefore, we conclude that the combinational treatment of SH003 with doxorubicin shows the synergism in TNBC treatment, and suggest that SH003 can be used together with conventional anti-cancer drugs in chemotherapeutic approaches. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Extratos Vegetais/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Angelica , Animais , Antineoplásicos/farmacologia , Apoptose , Astrágalo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Extratos Vegetais/farmacologia , Trichosanthes , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to interact with the oral anticoagulant warfarin and can cause a serious bleeding complication. In this study, we evaluated the risk factors for international normalized ratio (INR) increase, which is a surrogate marker of bleeding, after addition of an NSAID in a total of 98 patients who used warfarin. Patient age, sex, body mass index, maintenance warfarin dose, baseline INR, coadministered medications, underlying diseases, and liver and kidney functions were evaluated for possible risk factors with INR increase > or =15.0% as the primary end-point. Of the 98 patients, 39 (39.8%) showed an INR elevation of > or =15.0% after adding a NSAID to warfarin therapy. Multivariate analysis showed that high maintenance dose (>40 mg/week) of warfarin (P=0.001), the presence of coadministered medications (P=0.024), the use of meloxicam (P=0.025) and low baseline INR value (P=0.03) were the risk factors for INR increase in respect to NSAID-warfarin interaction. In conclusion, special caution is required when an NSAID is administered to warfarin users if patients are taking warfarin >40 mg/week and other medications interacting with warfarin.
Assuntos
Anti-Inflamatórios não Esteroides , Anticoagulantes , Hemorragia/induzido quimicamente , Varfarina , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Meloxicam , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Tiazinas/efeitos adversos , Tiazinas/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Varfarina/efeitos adversos , Varfarina/uso terapêuticoRESUMO
Progression of chronic myeloid leukemia, marked by the oncogenic BcrAbl mutation, is tightly associated with an alteration of the p53 pathway. It is known that butein extracted from various plants represses cancer growth. Although the anticancer effects of butein are widely accepted, the mechanisms by which butein induces apoptosis of chronic myeloid leukemia cells remains to be elucidated. The present study demonstrated that butein-induced apoptosis was mediated by p53. KBM5 chronic myeloid leukemia (CML) cells expressing wild-type p53 were more sensitive to butein compared with p53-null K562 CML cells in terms of apoptotic cell death. In addition, butein arrested KBM5 cells at S-phase and altered the expression levels of certain cyclins and the p53-downstream targets, MDM2 and p21. In addition, while butein reduced the protein expression of MDM2 in the KBM5 and K562 cells, it resulted in proteasome-independent MDM2 degradation in p53-expressing KBM5 cells, however, not in p53-null K562 cells. Therefore, the present study suggested that p53 causes the butein-mediated apoptosis of leukemic cells.
Assuntos
Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteína Supressora de Tumor p53/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismoRESUMO
Despite its therapeutic advantages, chemotherapy can also cause adverse effects, including anorexia and loss of appetite. Although numerous patients with cancer have been reported to suffer from anorexia during or following chemotherapy, treatment options for anorexia remain to be determined. In Asian countries, traditional medicines are widely used to treat problems with appetite; sip-jeon-dea-bo-tang (SJDBT) is one of those medicines used for the treatment of anorexia. The present study demonstrated that SJDBT ameliorated cisplatin-induced anorexia. In a mouse model of chemotherapy-induced anorexia, oral administration of SJDBT prevented the cisplatin-induced reduction of food intake, inhibiting weight loss. The results of multiplex assays showed that SJDBT only altered the levels of interleukin (IL)-6 and leptin in the serum and fat tissue. In addition, SJDBT maintained the serum leptin level and increased the serum IL-6 level, whereas cisplatin reduced the levels of both serum leptin and IL6. Furthermore, SJDBT was revealed to increase the levels of leptin and IL-6 in the fat tissue by activating the JAK1/STAT3 signaling pathway. In conclusion, the present results revealed that SJDBT ameliorated cisplatin-induced anorexia, suggesting its usefulness in the prevention of anorexia during chemotherapy.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Anorexia/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Interleucina-6/biossíntese , Janus Quinase 1/metabolismo , Leptina/biossíntese , Fator de Transcrição STAT3/metabolismo , Animais , Anorexia/tratamento farmacológico , Anorexia/etiologia , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Modelos Animais de Doenças , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacosRESUMO
Danggui-Sayuk-Ga-Osuyu-Senggang-Tang (DSGOST), one of the traditional Chinese medicines, has long been prescribed for patients suffering from Raynaud phenomenon (RP) in Northeast Asian countries, including China, Japan and Korea. Although a previous in vitro study from our laboratory revealed that DSGOST prevents cold (25ËC)induced RhoA activation and endothelin1 (ET1) production in endothelial cells (ECs), the mechanisms by which DSGOST is able to alleviate the symptoms of RP have yet to be fully elucidated. The present study aimed to demonstrate that DSGOST regulates RhoAmediated pathways in coldexposed pericytes. In pericytes, DSGOST amplified coldinduced RhoA activation, while markedly reducing ET1induced RhoA activation. Additionally, DSGOSTmediated regulation of RhoA was closely associated with Rhoassociated, coiledcoilcontaining protein kinase 1 (ROCK1)/testisspecific kinase 1 (TESK1)/PDXP, but not with LIM domain kinase 1/2 (LIMK1/2), cofilin and myosin light chain (MLC). Thus, DSGOST activation of RhoA/ROCK1/TESK1/PDXP in coldexposed pericytes appeared to be crucial for treating vessel contraction. In addition, the DSGOST effect on the RhoAmediated pathway in coldinduced human umbilical vein endothelial cells or human dermal microvascular endothelial cells was similar to that in ET1treated pericytes, but not in coldinduced pericytes. The results of the present study further confirmed that DSGOST inhibits coldinduced contraction of the mouse tail vein in vivo. Furthermore, DSGOST treatment reduced coldinduced expression of the α2cadrenergic receptor in mouse tail vessels. Therefore, the data in the present study suggest that DSGOST may be useful for the treatment of RPlike disease.