Molecular Cancer Therapeutics
1535-7163
1538-8514
Mỹ
Cơ quản chủ quản: American Association for Cancer Research Inc. , AMER ASSOC CANCER RESEARCH
Lĩnh vực:
Cancer ResearchOncology
Phân tích ảnh hưởng
Thông tin về tạp chí
Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.
Các bài báo tiêu biểu
GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models Abstract
The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. Human tumor cells treated with GSK1070916 show dose-dependent inhibition of phosphorylation on serine 10 of Histone H3, a substrate specific for Aurora B kinase. Moreover, GSK1070916 inhibits the proliferation of tumor cells with EC50 values of <10 nmol/L in over 100 cell lines spanning a broad range of tumor types. Although GSK1070916 has potent activity against proliferating cells, a dramatic shift in potency is observed in primary, nondividing, normal human vein endothelial cells, consistent with the proposed mechanism. We further determined that treated cells do not arrest in mitosis but instead fail to divide and become polyploid, ultimately leading to apoptosis. GSK1070916 shows dose-dependent inhibition of phosphorylation of an Aurora B–specific substrate in mice and consistent with its broad cellular activity, has antitumor effects in 10 human tumor xenograft models including breast, colon, lung, and two leukemia models. These results show that GSK1070916 is a potent Aurora B/C kinase inhibitor that has the potential for antitumor activity in a wide range of human cancers. [Mol Cancer Ther 2009;8(7):1808–17]
Tập 8 Số 7 - Trang 1808-1817 - 2009
Classification of anti-estrogens according to intramolecular FRET effects on phospho-mutants of estrogen receptor α Abstract Anti-estrogen resistance is a major clinical problem in the treatment of breast cancer. In this study, fluorescence resonance energy transfer (FRET) analysis, a rapid and direct way to monitor conformational changes of estrogen receptor α (ERα) upon anti-estrogen binding, was used to characterize resistance to anti-estrogens. Nine different anti-estrogens all induced a rapid FRET response within minutes after the compounds have liganded to ERα in live cells, corresponding to an inactive conformation of the ERα. Phosphorylation of Ser305 and/or Ser236 of ERα by protein kinase A (PKA) and of Ser118 by mitogen-activated protein kinase (MAPK) influenced the FRET response differently for the various anti-estrogens. PKA and MAPK are both associated with resistance to anti-estrogens in breast cancer patients. Their respective actions can result in seven different combinations of phospho-modifications in ERα where the FRET effects of particular anti-estrogen(s) are nullified. The FRET response provided information on the activity of ERα under the various anti-estrogen conditions as measured in a traditional reporter assay. Tamoxifen and EM-652 were the most sensitive to kinase activities, whereas ICI-182,780 (Fulvestrant) and ICI-164,384 were the most stringent. The different responses of anti-estrogens to the various combinations of phospho-modifications in ERα elucidate why certain anti-estrogens are more prone than others to develop resistance. These data provide new insights into the mechanism of action of anti-hormones and are critical for selection of the correct individual patient-based endocrine therapy in breast cancer. [Mol Cancer Ther 2007;6(5):1526–33]
Tập 6 Số 5 - Trang 1526-1533 - 2007
Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy Abstract
The proteasome and the autophagy systems are two evolutionarily conserved mechanisms for degrading intracellular materials. They are functionally coupled and suppression of the proteasome promotes autophagy. Although suppression of the proteasome leads to cell death, suppression of autophagy can be either prodeath or prosurvival. To understand the underlining mechanism of this dichotomy and its potential clinical implications, we treated various transformed and nontransformed human cells with proteasome inhibitors. We found that whether autophagy served a prosurvival role in this scenario was contingent on the cellular oncogenic status. Thus, autophagy suppression enhanced apoptosis induced by proteasome inhibitors in transformed cells, but not in nontransformed cells. Oncogenic transformation enhanced the ability of cells to initiate autophagy in response to stress, reflecting a stronger dependence of transformed cells on autophagy for survival. Indeed, a combined use of bortezomib, the only Food and Drug Administration–approved proteasome inhibitor for clinical use, and chloroquine, which inhibits autophagy by disturbing lysosomal functions, suppressed tumor growth more significantly than either agent alone in a xenograft model. These findings indicate that suppression of both intracellular degradation systems could constitute a novel strategy for enhanced cancer control in a tumor-specific way. [Mol Cancer Ther 2009;8(7):2036–45]
Tập 8 Số 7 - Trang 2036-2045 - 2009
A role for macroautophagy in protection against 4-hydroxytamoxifen–induced cell death and the development of antiestrogen resistance Abstract
This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor–positive (ER+) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER+ breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT–induced cell death, but not 4-OHT–induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT–resistant cells selected from ER+ breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER+, 4-OHT–resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER+ breast cancer. [Mol Cancer Ther 2008;7(9):2977–87]
Tập 7 Số 9 - Trang 2977-2987 - 2008
Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug? Abstract
Metformin is the most widely used antidiabetic drug in the world, and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. First, epidemiological studies show a decrease in cancer incidence in metformin-treated patients. Second, metformin decreases insulin resistance and indirectly reduces insulin level, a beneficial effect because insulin promotes cancer cell growth. Third, several reports outline a direct inhibitory effect of metformin on cancer cell growth and an antitumoral action. Finally, metformin activates the AMP activated protein kinase (AMPK) pathway, a major sensor of the energetic status of the cell, which has been proposed as a promising therapeutic target in cancer. Mol Cancer Ther; 9(5); 1092–99. ©2010 AACR.
Tập 9 Số 5 - Trang 1092-1099 - 2010
Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy Abstract
Human malignant melanoma has poor prognosis because of resistance to apoptosis and therapy. We describe identification of the expression profile of 1,037 mitochondria-focused genes and 84 survival-apoptosis genes in 21 malignant melanoma cell lines and 3 normal melanocyte controls using recently developed hMitChip3 cDNA microarrays. Unsupervised hierarchical clustering analysis of 1,037 informative genes, and 84 survival-apoptosis genes, classified these malignant melanoma cell lines into type A (n = 12) and type B (n = 9). Three hundred fifty-five of 1,037 (34.2%) genes displayed significant (P ≤ 0.030; false discovery rate ≤ 3.68%) differences (±≥2.0-fold) in average expression, with 197 genes higher and 158 genes lower in type A than in type B. Of 84 genes with known survival-apoptosis functions, 38 (45.2%) displayed the significant (P < 0.001; false discovery rate < 0.15%) difference. Antiapoptotic (BCL2, BCL2A1, PPARD, and RAF1), antioxidant (MT3, PRDX5, PRDX3, GPX4, GLRX2, and GSR), and proapoptotic (BAD, BNIP1, APAF1, BNIP3L, CASP7, CYCS, CASP1, and VDAC1) genes expressed at higher levels in type A than in type B, whereas the different set of antiapoptotic (PSEN1, PPP2CA, API5, PPP2R1B, PPP2R1A, and FIS1), antioxidant (HSPD1, GSS, SOD1, ATOX1, and CAT), and proapoptotic (ENDOG, BAK1, CASP2, CASP4, PDCD5, HTRA2, SEPT4, TNFSF10, and PRODH) genes expressed at lower levels in type A than in type B. Microarray data were validated by quantitative reverse transcription-PCR. These results showed the presence of two types of malignant melanoma, each with a specific set of dysregulated survival-apoptosis genes, which may prove useful for development of new molecular targets for therapeutic intervention and novel diagnostic biomarkers for treatment and prognosis of malignant melanoma.[Mol Cancer Ther 2009;8(5):OF1–13]
Tập 8 Số 5 - Trang 1292-1304 - 2009
C35 (<i>C17orf37</i>) is a novel tumor biomarker abundantly expressed in breast cancer Abstract
Identification of shared tumor-specific targets is useful in developing broadly applicable therapies. In a study designed to identify genes up-regulated in breast cancer, a cDNA clone corresponding to a novel gene C35 (C17orf37) was selected by representational difference analysis of tumor and normal human mammary cell lines. Abundant expression of C35 transcript in tumors was confirmed by Northern blot and real-time PCR. The C35 gene is located on chromosome 17q12, 505 nucleotides from the 3′ end of the ERBB2 oncogene, the antigenic target for trastuzumab (HerceptinTM) therapy. The chromosomal arrangement of the genes encoding C35 and ERBB2 is tail to tail. An open reading frame encodes a 12-kDa protein of unknown function. Immunohistochemical analysis detected robust and frequent expression of C35 protein, including 32% of grade 1 and 66% of grades 2 and 3 infiltrating ductal carcinomas of the breast (in contrast to 20% overexpressing HER-2/neu), 38% of infiltrating lobular carcinoma (typically HER-2/neu negative), as well as tumors arising in other tissues. C35 was not detected in 38 different normal human tissues, except Leydig cells in the testes and trace levels in a small percentage of normal breast tissue samples. The distinct and favorable expression profile of C35 spanning early through late stages of disease, including high frequency of overexpression in various breast carcinoma, abundant expression in distant metastases, and either absence or low level expression in normal human tissues, warrants further investigation of the relevance of C35 as a biomarker and/or a target for development of broadly applicable cancer-specific therapies. [Mol Cancer Ther 2006;5(11):2919–30]
Tập 5 Số 11 - Trang 2919-2930 - 2006
Pharmacologic inhibitors of IκB kinase suppress growth and migration of mammary carcinosarcoma cells<i>in vitro</i>and prevent osteolytic bone metastasis<i>in vivo</i> Abstract The NF-κB signaling pathway is known to play an important role in the regulation of osteoclastic bone resorption and cancer cell growth. Previous studies have shown that genetic inactivation of IκB kinase (IKK), a key component of NF-κB signaling, inhibits osteoclastogenesis, but the effects of pharmacologic IKK inhibitors on osteolytic bone metastasis are unknown. Here, we studied the effects of the IKK inhibitors celastrol, BMS-345541, parthenolide, and wedelolactone on the proliferation and migration of W256 cells in vitro and osteolytic bone destruction in vivo. All compounds tested inhibited the growth and induced apoptosis of W256 cells as evidenced by caspase-3 activation and nuclear morphology. Celastrol, BMS-345541, and parthenolide abolished IL1β and tumor necrosis factor α–induced IκB phosphorylation and prevented nuclear translocation of NF-κB and DNA binding. Celastrol and parthenolide but not BMS-345541 prevented the activation of both IKKα and IKKβ, and celastrol inhibited IKKα/β activation by preventing the phosphorylation of TAK1, a key receptor–associated factor upstream of IKK. Celastrol and parthenolide markedly reduced the mRNA expression of matrix metalloproteinase 9 and urinary plasminogen activator, and inhibited W256 migration. Administration of celastrol or parthenolide at a dose of 1 mg/kg/day suppressed trabecular bone loss and reduced the number and size of osteolytic bone lesions following W256 injection in rats. Histomorphometric analysis showed that both compounds decreased osteoclast number and inhibited bone resorption. In conclusion, pharmacologic inhibitors of IKK are effective in preventing osteolytic bone metastasis in this model and might represent a promising class of agents to the prevention and treatment of metastatic bone disease associated with breast cancer. [Mol Cancer Ther 2009;8(8):2339–47]
Tập 8 Số 8 - Trang 2339-2347 - 2009
Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells Abstract
We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399–412. ©2016 AACR.
Tập 15 Số 10 - Trang 2399-2412 - 2016
Glibenclamide Targets Sulfonylurea Receptor 1 to Inhibit p70S6K Activity and Upregulate KLF4 Expression to Suppress Non-Small Cell Lung Carcinoma Abstract
Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of ATP-sensitive potassium channels (KATP channels) and the receptor of antidiabetic drugs, such as glibenclamide, which induce insulin secretion in pancreatic β cells. However, the expression and role of SUR1 in cancer are unknown. In this study, we found that SUR1 expression was elevated in human non–small cell lung carcinoma (NSCLC) tissues and cell lines. SUR1 silencing suppressed the growth of NSCLC cells, while SUR1 overexpression promoted cell growth. Targeting SUR1 with glibenclamide suppressed cell growth, cell-cycle progression, epithelial–mesenchymal transition (EMT), and cell migration. Moreover, SUR1 directly interacted with p70S6K and upregulated p70S6K phosphorylation and activity. In addition, glibenclamide inhibited p70S6K, and overexpression of p70S6K partially reversed the growth-inhibiting effect of glibenclamide. Furthermore, glibenclamide upregulated the expression of the tumor suppressor Krüppel-like factor 4 (KLF4), and silencing KLF4 partially reversed the inhibitory effect of glibenclamide on cell growth, EMT, and migration. We found that SUR1 targeted p70S6K to downregulate KLF4 expression by enhancing DNA-methyltransferase 1–mediated methylation of the KLF4 promoter. Finally, in xenograft mouse models, SUR1 expression silencing or glibenclamide treatment inhibited the growth of A549 tumors, downregulated p70S6K activity, and upregulated KLF4 expression. These findings suggested that SUR1 expression was elevated in some NSCLC tissues and functioned as a tumor enhancer. Targeting SUR1 with glibenclamide inhibited NSCLC through downregulation of p70S6K activity and subsequent upregulation of the expression of the tumor suppressor gene KLF4. SUR1 can be developed as a new target for cancer therapy and glibenclamide has potential anticancer effects.
Tập 18 Số 11 - Trang 2085-2096 - 2019