RESUMO
A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.
Assuntos
Antineoplásicos/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Simulação de Acoplamento Molecular , Rotenona/química , Rotenona/metabolismo , Rotenona/farmacologia , Relação Estrutura-AtividadeRESUMO
Importance: Prospective assessment of treatments known to benefit patients in global clinical trials in specific racial groups is essential. Objective: To compare the efficacy, safety, and tolerability of adding pertuzumab to trastuzumab and docetaxel vs placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled phase 3 trial enrolled 329 women with ERBB2-positive early (T2-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) and primary tumor larger than 2 cm from March 14, 2016, to March 13, 2017. Analysis of the primary end point was performed on an intention-to-treat basis. Interventions: Before surgery, patients received 4 cycles of intravenous pertuzumab (840-mg loading dose and 420-mg maintenance doses), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), and docetaxel (75 mg/m2) or intravenous placebo, trastuzumab, and docetaxel every 3 weeks. After surgery, patients received 3 cycles of intravenous fluorouracil, epirubicin, and cyclophosphamide followed by 13 cycles of the same intravenous anti-ERBB2 therapy (pertuzumab and trastuzumab or placebo and trastuzumab) for up to 1 year. Main Outcomes and Measures: The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by disease category and hormone receptor status, was used to compare rates between treatment groups. Results: In total, 329 female patients were randomized (pertuzumab, 219; and placebo, 110; mean [SD] age, 48.8 [9.5] years). In the intention-to-treat population, total pathologic complete response rates were 39.3% (86 of 219) in the pertuzumab group and 21.8% (24 of 110) in the placebo group (difference, 17.5% [95% CI, 6.9%-28.0%]; P = .001). Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (83 of 218 [38.1%] vs 36 of 110 [32.7%]). Serious adverse events were reported in 10.1% of patients (22 of 218) in the pertuzumab group and 8.2% of patients (9 of 110) in the placebo group. Conclusions and Relevance: Treatment with pertuzumab, trastuzumab, and docetaxel resulted in a statistically significant improvement in the total pathologic complete response rate vs placebo, trastuzumab, and docetaxel for the neoadjuvant treatment of ERBB2-positive early or locally advanced breast cancer in Asian patients. Safety data were in line with the known pertuzumab safety profile and generally comparable between treatment groups. The PEONY trial adds to the totality of data showing the benefit of the pertuzumab regimen. Trial Registration: ClinicalTrials.gov identifier: NCT02586025.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Docetaxel/uso terapêutico , Receptor ErbB-2 , Trastuzumab/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ásia , Docetaxel/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Trastuzumab/efeitos adversos , Resultado do TratamentoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ulmus davidiana Nakai (UDN) is frequently used in the treatment of cancer in traditional oriental medicine. Although several reports indicate that UDN has inhibitory effects in some cancers, there has been no report on the inhibitory effects of UDN via both autophagy and apoptosis. MATERIALS AND METHODS: Cytotoxicity induced by UDN in human non-small cell lung cancer (NSCLC) H-1299 and H-460 cell lines was evaluated using the 2, 3-Bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT) assay and trypan blue exclusion assay. Induction of apoptosis was also investigated using Hoechst staining and annexin-V binding assay and was confirmed with western blot analysis. Induction of autophagy was investigated through observation of autophagy vacuoles under inverted phase-contrast microscopy and was confirmed by observing the formation of autophagy vacuoles under a fluorescence microscope using monodansylcadaverine (MDC) staining and western blot analysis. The in vivo anti-tumorigenic effect of UDN was investigated in an athymic nude mouse xenograft model using H-1299 NSCLC cells. RESULTS: UDN exhibited a marked inhibitory effect on cell growth in H-1299 and H-460 human NSCLC cell lines in a dose- and time-dependent manner in vitro and in vivo. It induced not only apoptosis, but also autophagy in both H-1299 and H-460 cells in a dose-dependent manner. UDN-mediated autophagy led to the accumulation of autophagosome, resulting in apoptosis induction and cell death. CONCLUSIONS: From our current knowledge, we are the first to demonstrate that UDN has the potential to induce both autophagy and apoptosis in H-1299 and H-460 human NSCLC cell lines. We suggest that UDN can be considered a potential candidate for lung cancer-specific chemotherapy with efficacy as a cytotoxic agent.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Ulmus/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Nus , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Numerous studies have been performed to identify the microenvironment of solid tumors, which is responsible for the insufficient delivery of anticancer drugs to tumor cells due to the poorly organized vasculature and the increased interstitial fluid pressure. As a result, the extravasation of convection-dependent agents including NPs is severely limited. Therefore, we have demonstrated the feasibility of targeting an enhancement of docetaxel-loaded Pluronic nanoparticles (NPs) using high-intensity focused ultrasound (HIFU) as an external stimulus-induced clinical system in tumor tissue. The efficient extravasation of NPs into the interior cells in tumor tissue was induced by relatively low HIFU exposure without apparent acute tissue damage. The enhanced targeting of NPs with near-infrared fluorescence dye was observed in tumor-bearing mice with various HIFU exposures. As a result, the greatest accumulation of NPs at the tumor tissue was observed at an HIFU exposure of 20 W/cm(2). However, the tumor tissue above at 20 W/cm(2) appeared to be destroyed and the tumor targetability of NPs was significantly decreased owing to thermal ablation with necrosis, resulting in the destruction of the tumor tissue and the blood vessels. In particular, a cross-sectional view of the tumor tissue verified that the NPs migrated into the middle of the tumor tissue upon HIFU exposure. The preliminary results here demonstrate that HIFU exposure through non-thermal mechanisms can aid with the extravasation of NPs into the interior cells of tumors and increase the therapeutic effect in enhanced and targeted cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/terapia , Sistemas de Liberação de Medicamentos/métodos , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Poloxâmero/química , Taxoides/farmacologia , Animais , Carcinoma de Células Escamosas/patologia , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Masculino , Camundongos , Transplante de Neoplasias , Polissorbatos/química , Óleo de Soja/química , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: This study evaluated the incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) of TAC compared with FAC following primary surgery for node positive breast cancer patients in Korea. MATERIALS AND METHODS: A cost-effectiveness analysis was performed using the Markov model from the combined view of Korean National Health Insurance and patients. The model allowed assessment from the beginning of the first cycle of adjuvant chemotherapy following primary surgery until death. Relevant clinical data were obtained from the clinical trial BCIRG 001 and data for local treatment patterns and direct medical costs were obtained from three Korean hospitals. RESULTS: Over a life time horizon, the life expectancy of TAC was 0.9 years longer than that of FAC. The ICER was 8,025,879 Korean won (KW, 6,573 euro) per life year gained and the ICUR was 8,885,794 KW (7,277 euro) per QALY gained when the cost and effectiveness were discounted at 5%. The model was most sensitive to the percent patient receiving prophylactic granulocyte colony stimulating factor (G-CSF) in TAC arm and the ICUR was 12,119,561 KW (9,926 euro) when assuming 100%. CONCLUSIONS: TAC appears to be cost-effective in the management of early breast cancer in Korea.