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1.
Biochem Biophys Res Commun ; 415(1): 163-7, 2011 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-22027148

RESUMO

Inflammatory breast cancer is driven by pro-angiogenic and pro-inflammatory cytokines. One of them Interleukin-6 (IL-6) is implicated in cancer cell proliferation and survival, and promotes angiogenesis, inflammation and metastasis. While IL-6 has been shown to be upregulated by several oncogenes, the mechanism behind this phenomenon is not well characterized. Here we demonstrate that the pleotropic Serine/Threonine kinase CK2 is implicated in the regulation of IL-6 expression in a model of inflammatory breast cancer. We used siRNAs targeted toward CK2 and a selective small molecule inhibitor of CK2, CX-4945, to inhibit the expression and thus suppress the secretion of IL-6 in in vitro as well as in vivo models. Moreover, we report that in a clinical trial, CX-4945 was able to dramatically reduce IL-6 levels in plasma of an inflammatory breast cancer patient. Our data shed a new light on the regulation of IL-6 expression and position CX-4945 and potentially other inhibitors of CK2, for the treatment of IL-6-driven cancers and possibly other diseases where IL-6 is instrumental, including rheumatoid arthritis.


Assuntos
Caseína Quinase II/metabolismo , Neoplasias Inflamatórias Mamárias/metabolismo , Interleucina-6/biossíntese , Animais , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/genética , Linhagem Celular Tumoral , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/sangue , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Camundongos , Camundongos Endogâmicos BALB C , Naftiridinas/uso terapêutico , Fenazinas , Inibidores de Proteínas Quinases/uso terapêutico , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/metabolismo
2.
Mol Cancer Ther ; 6(9): 2505-14, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17766839

RESUMO

The phosphatidylinositol 3-kinase (PI3K) pathway is activated in many human tumors and mediates processes such as cell proliferation, survival, adhesion, and motility. The natural product, wortmannin, has been widely used to study the functional consequences of PI3K inhibition in both normal and transformed cells in culture but is not a suitable cancer chemotherapeutic agent due to stability and toxicity issues. PX-866, an improved wortmannin analogue, displays significant antitumor activity in xenograft models. Here, we directly compare PX-866 and wortmannin in human cancer cell lines cultured in monolayer or as three-dimensional spheroids. Both PI3K inhibitors failed to inhibit monolayer cell growth at concentrations up to 100 nmol/L but strongly suppressed spheroid growth at low nanomolar concentrations, with PX-866 showing greater potency than wortmannin. Relative to wortmannin, PX-866 treatment results in a more sustained loss of Akt phosphorylation, suggesting that the increased potency of PX-866 is related to a more durable inhibition of PI3K signaling. PX-866 and wortmannin both inhibit spheroid growth without causing cytotoxicity, similar to known cytostatic agents, such as rapamycin. PX-866 also inhibits cancer cell motility at subnanomolar concentrations. These findings suggest that the antitumor activities of PX-866 stem from prolonged inhibition of the PI3K pathway and inhibition of cell motility. In addition, we propose that the use of three-dimensional tumor models is more predictive of in vivo growth inhibition by PI3K inhibitors in cancer cell lines lacking phosphatase and tensin homologue activity or expression.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Gonanos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Esferoides Celulares/efeitos dos fármacos , Androstadienos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Wortmanina
3.
Mol Cancer Ther ; 11(4): 994-1005, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22267551

RESUMO

Drug combination therapies are commonly used for the treatment of cancers to increase therapeutic efficacy, reduce toxicity, and decrease the incidence of drug resistance. Although drug combination therapies were originally devised primarily by empirical methods, the increased understanding of drug mechanisms and the pathways they modulate provides a unique opportunity to design combinations that are based on mechanistic rationale. We have identified protein kinase CK2 as a promising therapeutic target for combination therapy, because CK2 regulates not just one but many oncogenic pathways and processes that play important roles in drug resistance, including DNA repair, epidermal growth factor receptor signaling, PI3K/AKT/mTOR signaling, Hsp90 machinery activity, hypoxia, and interleukin-6 expression. In this article, we show that CX-4945, a clinical stage selective small molecule inhibitor of CK2, blocks the DNA repair response induced by gemcitabine and cisplatin and synergizes with these agents in models of ovarian cancer. Mechanistic studies show that the enhanced activity is a result of inactivation of XRCC1 and MDC1, two mediator/adaptor proteins that are essential for DNA repair and that require phosphorylation by CK2 for their function. These data position CK2 as a valid pharmacologic target for intelligent drug combinations and support the evaluation of CX-4945 in combination with gemcitabine and platinum-based chemotherapeutics in the clinical setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Caseína Quinase II/antagonistas & inibidores , Reparo do DNA/efeitos dos fármacos , Naftiridinas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Quinase do Ponto de Checagem 2 , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Naftiridinas/administração & dosagem , Neoplasias/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Fenazinas , Fosforilação , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Res ; 71(4): 1418-30, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21159662

RESUMO

Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell- and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells. CX-5461 selectively inhibits Pol I-driven transcription relative to Pol II-driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment.


Assuntos
Benzotiazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Naftiridinas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , RNA Polimerase I/antagonistas & inibidores , RNA Ribossômico/biossíntese , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzotiazóis/administração & dosagem , Benzotiazóis/uso terapêutico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular/métodos , Naftiridinas/administração & dosagem , Naftiridinas/uso terapêutico , Neoplasias/metabolismo , RNA Polimerase I/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Res ; 69(19): 7653-61, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19738048

RESUMO

Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial.


Assuntos
Benzoxazinas/farmacologia , Neoplasias/tratamento farmacológico , Quinolonas/farmacologia , RNA Ribossômico/antagonistas & inibidores , RNA Ribossômico/biossíntese , Animais , Apoptose/efeitos dos fármacos , Benzoxazinas/farmacocinética , Linhagem Celular Tumoral , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/metabolismo , DNA Polimerase I/antagonistas & inibidores , DNA Polimerase I/genética , DNA Polimerase I/metabolismo , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Feminino , Quadruplex G/efeitos dos fármacos , Células HL-60 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Neoplasias/genética , Neoplasias/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Quinolonas/farmacocinética , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Telômero/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Nucleolina
6.
Bioorg Med Chem ; 12(17): 4749-59, 2004 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15358300

RESUMO

Phosphoinositide 3-kinases (PI3-Ks) are an ubiquitous class of signaling enzymes that regulate diverse cellular processes including growth, differentiation, and motility. Physiological roles of PI3-Ks have traditionally been assigned using two pharmacological inhibitors, LY294002 and wortmannin. Although these compounds are broadly specific for the PI3-K family, they show little selectivity among family members, and the development of isoform-specific inhibitors of these enzymes has been long anticipated. Herein, we prepare compounds from two classes of arylmorpholine PI3-K inhibitors and characterize their specificity against a comprehensive panel of targets within the PI3-K family. We identify multiplex inhibitors that potently inhibit distinct subsets of PI3-K isoforms, including the first selective inhibitor of p110beta/p110delta (IC(50) p110beta=0.13 microM, p110delta=0.63 microM). We also identify trends that suggest certain PI3-K isoforms may be more sensitive to potent inhibition by arylmorpholines, thereby guiding future drug design based on this pharmacophore.


Assuntos
Androstadienos/farmacologia , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Isoformas de Proteínas/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Células Cultivadas , Concentração Inibidora 50 , Metabolismo dos Lipídeos , Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Wortmanina
7.
Org Biomol Chem ; 2(13): 1911-20, 2004 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-15227545

RESUMO

A series of viridin analogs was prepared from wortmannin by nucleophilic ring opening at C(20) and evaluated against the signaling kinases PI-3-kinase and mTOR. Several subnanomolar enzyme inhibitors with orders of magnitude selectivity for PI-3-kinase and strong cytotoxic activity against four cancer cell lines were identified. Among the ten most promising derivatives, six demonstrated lower liver toxicity and greater promise for inhibition of tumor cell growth than the lead structure wortmannin.


Assuntos
Androstadienos/química , Androstenos/síntese química , Androstenos/farmacologia , Bacteriocinas/síntese química , Bacteriocinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Alquilação , Androstadienos/farmacologia , Androstenos/química , Androstenos/toxicidade , Bacteriocinas/química , Bacteriocinas/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Fosfatidilinositóis/química , Fosfatidilinositóis/metabolismo , Inibidores de Proteínas Quinases/química , Especificidade por Substrato , Wortmanina
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