RESUMO
Breast cancer is one of the leading causes of cancer mortality worldwide, and triple-negative breast cancer (TNBC) is the most problematic subtype. There is an urgent need to develop novel drug candidates for TNBC. Marine toxins are a valuable source for drug discovery. We previously identified αO-conotoxin GeXIVA[1,2] from Conus generalis, which is a selective antagonist of α9 nicotinic acetylcholine receptors (nAChRs). Recent studies indicated that α9 nAChR expression is positively correlated with breast cancer development; thus, α9 nAChR could serve as a therapeutic target for breast cancer. In this study, we aimed to investigate the in vivo antitumor effects of GeXIVA[1,2] on TNBC and to elucidate its underlying anticancer mechanism. Our data showed that GeXIVA[1,2] effectively suppressed 4T1 tumor growth in vivo at a very low dose of 0.1 nmol per mouse. Our results uncovered that the antitumor mechanism of GeXIVA[1,2] simultaneously induced apoptosis and blocked proliferation. Further investigations revealed that GeXIVA[1,2]-induced Caspase-3-dependent apoptosis was achieved through regulating Bax/Bcl-2 balance, and GeXIVA[1,2]-inhibited proliferation was mediated by the downregulation of the AKT-mTOR, STAT3 and NF-κB signaling pathways. Our study provides valuable arguments to demonstrate the potential of GeXIVA[1,2] as a novel marine-derived anticancer drug candidate for the treatment of TNBC.
Assuntos
Apoptose , Proliferação de Células , Conotoxinas , NF-kappa B , Proteínas Proto-Oncogênicas c-akt , Fator de Transcrição STAT3 , Transdução de Sinais , Serina-Treonina Quinases TOR , Neoplasias de Mama Triplo Negativas , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Apoptose/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo , NF-kappa B/metabolismo , Feminino , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Proliferação de Células/efeitos dos fármacos , Conotoxinas/farmacologia , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Humanos , Antineoplásicos/farmacologiaRESUMO
Animal-derived venom, like snake venom, has been proven to be valuable natural resources for the drug development. Previously, snake venom was mainly investigated in its pharmacological activities in regulating coagulation, vasodilation, and cardiovascular function, and several marketed cardiovascular drugs were successfully developed from snake venom. In recent years, snake venom fractions have been demonstrated with anticancer properties of inducing apoptotic and autophagic cell death, restraining proliferation, suppressing angiogenesis, inhibiting cell adhesion and migration, improving immunity, and so on. A number of active anticancer enzymes and peptides have been identified from snake venom toxins, such as L-amino acid oxidases (LAAOs), phospholipase A2 (PLA2), metalloproteinases (MPs), three-finger toxins (3FTxs), serine proteinases (SPs), disintegrins, C-type lectin-like proteins (CTLPs), cell-penetrating peptides, cysteine-rich secretory proteins (CRISPs). In this review, we focus on summarizing these snake venom-derived anticancer components on their anticancer activities and underlying mechanisms. We will also discuss their potential to be developed as anticancer drugs in the future.
Assuntos
Antineoplásicos , Venenos de Serpentes , Humanos , Venenos de Serpentes/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Animais , Neoplasias/tratamento farmacológico , L-Aminoácido Oxidase/química , L-Aminoácido Oxidase/farmacologia , Apoptose/efeitos dos fármacos , Fosfolipases A2/metabolismo , Fosfolipases A2/química , Toxinas Biológicas/química , Toxinas Biológicas/farmacologiaRESUMO
Cancer is a major global public health problem with high morbidity. Depression is known to be a high-frequency complication of cancer diseases that decreases patients' life quality and increases the mortality rate. Therefore, antidepressants are often used as a complementary treatment during cancer therapy. During recent decades, various studies have shown that the combination of antidepressants and anticancer drugs increases treatment efficiency. In recent years, further emerging evidence has suggested that the modulation of autophagy serves as one of the primary anticancer mechanisms for antidepressants to suppress tumor growth. In this review, we introduce the anticancer potential of antidepressants, including tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). In particular, we focus on their autophagy-modulating mechanisms for regulating autophagosome formation and lysosomal degradation. We also discuss the prospect of repurposing antidepressants as anticancer agents. It is promising to repurpose antidepressants for cancer therapy in the future.
Assuntos
Antidepressivos , Neoplasias , Humanos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina , Antidepressivos Tricíclicos , Norepinefrina , Autofagia , Neoplasias/tratamento farmacológicoRESUMO
Cancer is a serious disease with high mortality and morbidity worldwide. Natural products have served as a major source for developing new anticancer drugs during recent decades. Magnolol, a representative natural phenolic lignan isolated from Magnolia officinali, has attracted considerable attention for its anticancer properties in recent years. Accumulating preclinical studies have demonstrated the tremendous therapeutic potential of magnolol via a wide range of pharmacological mechanisms against cancer. In this review, we summarized the latest advances in preclinical studies investigating anticancer properties of magnolol and described the important signaling pathways explaining its underlying mechanisms. Magnolol was capable of inhibiting cancer growth and metastasis against various cancer types. Magnolol exerted anticancer effects through inhibiting proliferation, inducing cell cycle arrest, provoking apoptosis, restraining migration and invasion, and suppressing angiogenesis. Multiple signaling pathways were also involved in the pharmacological actions of magnolol against cancer, such as PI3K/Akt/mTOR signaling, MAPK signaling and NF-κB signaling. Based on this existing evidence summarized in the review, we have conclusively confirmed magnolol had a multi-target anticancer effect against heterogeneous cancer disease. It is promising to develop magnolol as a drug candidate for cancer therapy in the future.
Assuntos
Antineoplásicos , Produtos Biológicos , Lignanas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Produtos Biológicos/farmacologia , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Lignanas/farmacologia , Lignanas/uso terapêutico , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
In order to identify two putative glutathione S-transferase (GSTs) genes in Fusarium oxysporum f. sp. cubense race 4 (Foc4), cDNA sequences of the entire coding regions of the two genes were cloned from Foc4 using RT-PCR method. Subsequently, the two genes were named Fogst1 and Fogst2 respectively. The length of open reading frame of Fogst1 was 609 bp and encoded a protein including 202 amino acid residues, Fogst2 possessed an open reading frame with 693 bp which encoded a 230-amino acid protein. Phylogenetic analysis showed that Fogst1 belonged to sigma (σ) subtype members of the GSTs superfamily, and Fogst2 was a new member of an unknown subfamily in the GSTs superfamily. To verify the expression of Fogst1 and Fogst2, the recombinant prokaryotic expression vector pET28a-Fogst1 and pET28a-Fogst2 were constructed and transformed into Escherichia coli expression strain BL21(DE3). The soluble recombinant proteins Fogst1 and Fogst2 were obtained after being induced by IPTG. GSTs activity assays showed that both of the two recombinant proteins had specific activity with CDNB. For real time RT- PCR analysis, the mycelium samples of Foc4 were collected after treatment by H2O2 for 1, 5, 12, 24 hours. The results showed that the expression of Fogst1 and Fogst2 were significantly up-regulated in the first 5 hours, and then decreased and returned to normal level. These results suggested that Fogst1 and Fogst2 may be involved in the process of Foc4 resistance to exogenous oxidative stress.
Assuntos
Proteínas Fúngicas/metabolismo , Fusarium/enzimologia , Glutationa Transferase/metabolismo , Estresse Oxidativo , Sequência de Aminoácidos , Clonagem Molecular , DNA Complementar/genética , Proteínas Fúngicas/genética , Fusarium/genética , Glutationa Transferase/genética , Peróxido de Hidrogênio , Filogenia , Proteínas RecombinantesRESUMO
Following determination of trypsin inhibitory activity, a serine protease inhibitor was purified and characterized from frog Duttaphrynus melanostictus serum. It was identified as serum albumin, with molecular weight of 67 kDa (DmA-serum). Different from bovine serum albumin, DmA-serum potently inhibited trypsin with similar K(i) values around 1.6 × 10â»7 M. No inhibitory effect on thrombin, chymotrypsin, elastase and subtilisin was observed under the assay conditions. The N-terminal amino acid is EAEPHSRI. Subsequently, a protein with same N-terminal amino acid was purified from skin, termed as DmA-skin. However, DmA-skin is distinct from DmA-serum by binding of a haem b (0.5 mol/mol protein), and with low trypsin inhibitory activity. Frog albumin is distributed in frog skin and exhibited trypsin inhibitory activity, suggesting that it plays important roles in skin physiological functions, like water economy, metabolite exchange and osmoregulation, etc.
Assuntos
Anuros , Albumina Sérica/química , Albumina Sérica/isolamento & purificação , Pele/química , Inibidores da Tripsina/isolamento & purificação , Animais , Feminino , Cinética , Masculino , Peso Molecular , Inibidores da Tripsina/químicaRESUMO
Mitogen-activated protein kinases (MAPKs) are evolutionarily conserved enzymes in cell signal transduction connecting cell-surface receptors to critical regulatory targets within cells and control cell survival, adaptation, and proliferation. Previous studies revealed that zinc-finger proteins are involved in the regulation of the MAPK signaling pathways. Here, we report the identification and characterization of a novel human zinc-finger protein, ZNF641. The cDNA of ZNF641 is 4.9kb, encoding 438 amino acids in the nucleus. The protein is highly conserved in evolution across different vertebrate species from mouse to human. Northern blot analysis indicates that ZNF641 is expressed in most of the examined human tissues, with a high level in skeletal muscle. Overexpression of pCMV-Tag2B-ZNF641 in the COS-7 cells activates the transcriptional activities of AP-1 and SRE. Deletion analysis indicates that the linker between KRAB box and C(2)H(2)-type zinc-fingers represents the basal activation domain. These results suggest that ZNF641 may be a positive regulator in MAPK-mediated signaling pathways that lead to the activation of AP-1 and SRE.