Molecular Cancer Therapeutics
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Kaempferol gây ra quá trình apoptosis trong các tế bào u nguyên bào thần kinh đệm qua stress oxy hóa Tóm tắt
Mặc dù đã có những tiến bộ gần đây trong việc hiểu rõ cơ chế phân tử liên quan đến tiến triển của u nguyên bào thần kinh đệm, tiên lượng của khối u não ác tính nhất này vẫn tiếp tục ảm đạm. Vì flavonoid kaempferol được biết đến với khả năng ức chế sự phát triển của một số bệnh ung thư ở người, chúng tôi đã nghiên cứu tác động của kaempferol lên các tế bào u nguyên bào thần kinh đệm ở người. Kaempferol đã gây ra quá trình apoptosis trong các tế bào glioma bằng cách nâng cao stress oxy hóa nội bào. Stress oxy hóa gia tăng được đặc trưng bởi sự sản sinh gia tăng của các loại oxy phản ứng (ROS) đi kèm với sự giảm các chất gạt oxy hóa như superoxide dismutase (SOD-1) và thioredoxin (TRX-1). Việc giảm biểu hiện của SOD-1 và TRX-1 nhờ RNA can thiệp ngắn (siRNA) làm tăng sinh ROS và độ nhạy cảm của các tế bào glioma với quá trình apoptosis do kaempferol gây ra. Dấu hiệu của apoptosis bao gồm giảm biểu hiện của Bcl-2 và thay đổi điện thế màng ty thể với sự gia tăng của caspase-3 hoạt động và biểu hiện của poly(ADP-ribose) polymerase đã bị phân cắt. Sự thay đổi cả điện thế màng plasma và độ linh động màng trong các tế bào được xử lý với kaempferol. Kaempferol ức chế biểu hiện của cytokine tiền viêm interleukin-6 và chemokine interleukin-8, protein chemotactic đơn bào-1, và quy định về hoạt hóa, T-cell bình thường có biểu hiện và tiết ra. Kaempferol ức chế sự di cư của tế bào glioma theo cách phụ thuộc vào ROS. Đáng chú ý, kaempferol tăng cường tác dụng độc của chất hóa trị liệu doxorubicin bằng cách tăng cường độc tính của ROS và giảm sự xuất hiện của doxorubicin. Vì tác dụng độc của cả kaempferol và doxorubicin đều được tăng cường khi sử dụng kết hợp, nghiên cứu này đưa ra khả năng trị liệu kết hợp có cơ sở là tăng cường sự rối loạn redox làm chiến lược tiêu diệt các tế bào glioma. [Mol Cancer Ther 2007;6(9):2544–53]
Molecular Cancer Therapeutics - Tập 6 Số 9 - Trang 2544-2553 - 2007
#Glioblastoma #Apoptosis #Oxidative Stress #Flavonoid Kaempferol #ROS #SOD-1 #TRX-1 #Cytokine #Chemokine #Doxorubicin
Targeting Interleukin-4 Receptor α with Hybrid Peptide for Effective Cancer Therapy Abstract
Interleukin-4 receptor α (IL-4Rα) chain is highly expressed on the surface of various human solid tumors. We designed a novel hybrid peptide termed IL-4Rα–lytic peptide that targets the IL-4Rα chain. The IL-4Rα–lytic peptide contains a target moiety to bind to IL-4Rα and a cellular toxic lytic peptide that selectively kills cancer cells. The anticancer activity of the IL-4Rα–lytic peptide was evaluated in vitro and in vivo. It was found that the IL-4Rα–lytic peptide has cytotoxic activity in cancer cell lines expressing IL-4Rα, determined by quantitative real-time PCR. The IC50 ratios of the lytic peptide to the IL-4Rα–lytic peptide correlated well with the expression levels of IL-4Rα on cancer cells (r = 0.80). In addition, IL-4Rα–lytic peptide administered either intratumoraly or intravenously significantly inhibited tumor growth in xenograft model of human pancreatic cancer (BXPC-3) in mice. These results indicate that the IL-4Rα–lytic peptide generated in this study has a potent and selective anticancer potential against IL-4Rα–positive solid cancers. Mol Cancer Ther; 11(1); 235–43. ©2011 AACR.
Molecular Cancer Therapeutics - Tập 11 Số 1 - Trang 235-243 - 2012
Preclinical validation of anti-TMEFF2-auristatin E–conjugated antibodies in the treatment of prostate cancer Abstract
Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor–like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B–sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.
Molecular Cancer Therapeutics - Tập 3 Số 8 - Trang 921-932 - 2004
KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations Abstract
Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75− (CD34+) and CD34−p75− (CD34−) tumor subpopulations were characterized as melanoma-propagating cells (MPC) that exhibit some of those key features. However, these two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemoresistance. In this study, we demonstrate that CD34+ and CD34− subpopulations carrying the BRAFV600E mutation confer differential sensitivity to targeted BRAF inhibition. Through elevated KDM5B expression, melanoma cells shift toward a more drug-tolerant, CD34− state upon exposure to BRAF inhibitor or combined BRAF inhibitor and MEK inhibitor treatment. KDM5B loss or inhibition shifts melanoma cells to the more BRAF inhibitor–sensitive CD34+ state. These results support that KDM5B is a critical epigenetic regulator that governs the transition of key MPC subpopulations with distinct drug sensitivity. This study also emphasizes the importance of continuing to advance our understanding of intratumor heterogeneity and ultimately develop novel therapeutics by altering the heterogeneous characteristics of melanoma.
Molecular Cancer Therapeutics - Tập 18 Số 3 - Trang 706-717 - 2019
Activation of Peroxisome Proliferator-Activated Receptor-β/δ (PPAR-β/δ) Inhibits Human Breast Cancer Cell Line Tumorigenicity Abstract
The effect of activation and overexpression of the nuclear receptor PPAR-β/δ in human MDA-MB-231 (estrogen receptor–negative; ER−) and MCF7 (estrogen-receptor-positive; ER+) breast cancer cell lines was examined. Target gene induction by ligand activation of PPAR-β/δ was increased by overexpression of PPAR-β/δ compared with controls. Overexpression of PPAR-β/δ caused a decrease in cell proliferation in MCF7 and MDA-MB-231 cells compared with controls, whereas ligand activation of PPAR-β/δ further inhibited proliferation of MCF7 but not MDA-MB-231 cells. Overexpression and/or ligand activation of PPAR-β/δ in MDA-MB-231 or MCF7 cells had no effect on experimental apoptosis. Decreased clonogenicity was observed in both MDA-MB-231 and MCF7 overexpressing PPAR-β/δ in response to ligand activation of PPAR-β/δ as compared with controls. Ectopic xenografts developed from MDA-MB-231 and MCF7 cells overexpressing PPAR-β/δ were significantly smaller, and ligand activation of PPAR-β/δ caused an even greater reduction in tumor volume as compared with controls. Interestingly, the decrease in MDA-MB-231 tumor size after overexpressing PPAR-β/δ and ligand activation of PPAR-β/δ correlated with increased necrosis. These data show that ligand activation and/or overexpression of PPAR-β/δ in two human breast cancer cell lines inhibits relative breast cancer tumorigenicity and provide further support for the development of ligands for PPAR-β/δ to specifically inhibit breast carcinogenesis. These new cell-based models will be invaluable tools for delineating the role of PPAR-β/δ in breast cancer and evaluating the effects of PPAR-β/δ agonists. Mol Cancer Ther; 13(4); 1008–17. ©2014 AACR.
Molecular Cancer Therapeutics - Tập 13 Số 4 - Trang 1008-1017 - 2014
Shikonin circumvents cancer drug resistance by induction of a necroptotic death Abstract
Defect in apoptotic signaling and up-regulation of drug transporters in cancer cells significantly limits the effectiveness of cancer chemotherapy. We propose that an agent inducing non-apoptotic cell death may overcome cancer drug resistance and showed that shikonin, a naturally occurring naphthoquinone, induced a cell death in MCF-7 and HEK293 distinct from apoptosis and characterized with (a) a morphology of necrotic cell death; (b) loss of plasma membrane integrity; (c) loss of mitochondrial membrane potentials; (d) activation of autophagy as a downstream consequence of cell death, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) that the cell death was prevented by a small molecule, necrostatin-1, that specifically prevents cells from necroptosis. The characteristics fully comply with those of necroptosis, a basic cell-death pathway recently identified by Degterev et al. with potential relevance to human pathology. Furthermore, we proved that shikonin showed a similar potency toward drug-sensitive cancer cell lines (MCF-7 and HEK293) and their drug-resistant lines overexpressing P-glycoprotein, Bcl-2, or Bcl-xL, which account for most of the clinical cancer drug resistance. To our best knowledge, this is the first report to document the induction of necroptosis by a small molecular compound to circumvent cancer drug resistance. [Mol Cancer Ther 2007;6(5):1641–9]
Molecular Cancer Therapeutics - Tập 6 Số 5 - Trang 1641-1649 - 2007
Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer Abstract Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor–positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2+ cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors. Mol Cancer Ther; 13(4); 890–901. ©2014 AACR.
Molecular Cancer Therapeutics - Tập 13 Số 4 - Trang 890-901 - 2014
A Pilot Clinical Study of Treatment Guided by Personalized Tumorgrafts in Patients with Advanced Cancer Abstract
Patients with many advanced solid cancers have very poor prognosis, and improvements in life expectancy are measured only in months. We have recently reported the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA-damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized tumorgraft generated from the patient's surgically resected tumor. Here, we extend the approach to patients with other advanced cancers. Tumors resected from 14 patients with refractory advanced cancers were propagated in immunodeficient mice and treated with 63 drugs in 232 treatment regimens. An effective treatment regimen in the xenograft model was identified for 12 patients. One patient died before receiving treatment, and the remaining 11 patients received 17 prospectively guided treatments. Fifteen of these treatments resulted in durable partial remissions. In 2 subjects, no effective treatments were found. Overall, there was a remarkable correlation between drug activity in the model and clinical outcome, both in terms of resistance and sensitivity. The data support the use of the personalized tumorgraft model as a powerful investigational platform for therapeutic decision making and to efficiently guide cancer treatment in the clinic. Mol Cancer Ther; 10(8); 1311–6. ©2011 AACR.
Molecular Cancer Therapeutics - Tập 10 Số 8 - Trang 1311-1316 - 2011
MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity <i>in vitro</i> and <i>in vivo</i> Abstract
Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759–68]
Molecular Cancer Therapeutics - Tập 7 Số 4 - Trang 759-768 - 2008
A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells Abstract
Single-chain alkylphospholipids, unlike conventional chemotherapeutic drugs, act on cell membranes to induce apoptosis in tumor cells. We tested four different alkylphospholipids, i.e., edelfosine, perifosine, erucylphosphocholine, and compound D-21805, as inducers of apoptosis in the mouse lymphoma cell line S49. We compared their mechanism of cellular entry and their potency to induce apoptosis through inhibition of de novo biosynthesis of phosphatidylcholine at the endoplasmic reticulum. Alkylphospholipid potency closely correlated with the degree of phosphatidylcholine synthesis inhibition in the order edelfosine > D-21805 > erucylphosphocholine > perifosine. In all cases, exogenous lysophosphatidylcholine, an alternative source for cellular phosphatidylcholine production, could partly rescue cells from alkylphospholipid-induced apoptosis, suggesting that phosphatidylcholine biosynthesis is a direct target for apoptosis induction. Cellular uptake of each alkylphospholipid was dependent on lipid rafts because pretreatment of cells with the raft-disrupting agents, methyl-β-cyclodextrin, filipin, or bacterial sphingomyelinase, reduced alkylphospholipid uptake and/or apoptosis induction and alleviated the inhibition of phosphatidylcholine synthesis. Uptake of all alkylphospholipids was inhibited by small interfering RNA (siRNA)–mediated blockage of sphingomyelin synthase (SMS1), which was previously shown to block raft-dependent endocytosis. Similar to edelfosine, perifosine accumulated in (isolated) lipid rafts independent on raft sphingomyelin content per se. However, perifosine was more susceptible than edelfosine to back-extraction by fatty acid-free serum albumin, suggesting a more peripheral location in the cell due to less effective internalization. Overall, our results suggest that lipid rafts are critical membrane portals for cellular entry of alkylphospholipids depending on SMS1 activity and, therefore, are potential targets for alkylphospholipid anticancer therapy. [Mol Cancer Ther 2007;6(8):2337–45]
Molecular Cancer Therapeutics - Tập 6 Số 8 - Trang 2337-2345 - 2007
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