Proteasome inhibitors in cancer therapy

Crawford, Lisa; Walker, Brian; Irvine, Alexandra

doi:10.1007/s12079-011-0121-7

Cited by 266 publications

(263 citation statements)

References 78 publications

(83 reference statements)

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“…NF-κB, a transcription factor, stimulates the expression of numerous genes associated with oxidative stress, immune responses, cytokine production and apoptosis (22,23). NF-κB belongs to the Rel family, which consists of p50, p52, c-Rel, p65 and RelB.…”

Section: Introductionmentioning

confidence: 99%

Melatonin treatment induces apoptosis through regulating the nuclear factor-κB and mitogen-activated protein kinase signaling pathways in human gastric cancer SGC7901 cells

et al. 2017

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Abstract. Melatonin, which is synthesized by the pineal gland and released into the blood, exhibits antitumor properties. However, the mechanisms underlying these effects, particularly in stomach cancer, remain unknown. In the present study, the effect of melatonin on the nuclear factor (NF)-κB signaling pathway and the mitogen-activated protein kinase signaling pathway, involving p38 and c-Jun-N-terminal kinase (JNK), were investigated in SGC7901 gastric cancer cells. In addition, the effect of melatonin on the survival, migration and apoptosis of these cells was investigated in vitro in order to evaluate the use of melatonin for the treatment of gastric cancer. The results of the present study revealed that melatonin decreased the viability and migration of SGC7901 cells. Furthermore, melatonin induced apoptosis. Melatonin was identified to elevate the expression levels of phosphorylated (p)-p38 and p-JNK protein, and decrease the expression level of nucleic p-p65. These results suggest that the protein levels of p65, p38 and JNK are associated with the survival of SGC7901 cells following treatment with melatonin. The optimal concentration of melatonin was demonstrated to be 2 mM, which significantly induced apoptosis following a 24 h treatment period. These findings suggest that conflicting growth signals in cells may inhibit the efficacy of melatonin in the treatment of gastric cancer. Therefore, adjunct therapy would be required to improve the efficacy of melatonin in the treatment of cancer. IntroductionGastric carcinoma is one of the most common types of malignancy, worldwide (1). In Asia, patients tend to be diagnosed at an average age of 66.8 years, and exhibit poor rates of survival (1). Gastric cancer is a refractory cancer and the third-leading cause of cancer-associated mortality in China (2). Gastric adenocarcinoma is the predominant type of gastric cancer and has limited treatment options (3). The typical treatments for gastric cancer, surgery and chemotherapy, only partially improve the overall survival of patients with this disease (4,5). Therefore, more effective drugs or comprehensive therapies are required (6).Melatonin is an indole hormone secreted by the pineal gland and was first identified in 1958 (7). Melatonin serves a significant role in a wide variety of biological processes, including sleep, immunomodulation, anti-inflammation and antioxidative stress (8-11). In addition, melatonin is an anticancer hormone and a potential target for cancer treatments (12). Several studies have revealed that melatonin is useful for the prevention of cancer (13,14). The antitumor ability of melatonin may be mediated by numerous mechanisms, including the activation of antioxidative stress, inhibition of migration and induction of apoptosis (15)(16)(17). Melatonin has also been demonstrated to suppress the growth, migration and invasion of SGC7901 gastric cancer cells in vitro (18), and to exert an apoptotic effect in the hepatocellular carcinoma HepG2 cell line (19). Additionally, the use of melatonin h...

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Section: Introductionmentioning

confidence: 99%

Melatonin treatment induces apoptosis through regulating the nuclear factor-κB and mitogen-activated protein kinase signaling pathways in human gastric cancer SGC7901 cells

et al. 2017

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“…This pathway is involved in the cell cycle, apoptosis, transcription, DNA repair, protein quality control, and antigen presentation (Crawford et al, 2011). The 26S proteasome complex regulates degradation of intracellular proteins involved in key regulatory cellular processes.…”

Section: Introductionmentioning

confidence: 99%

Apoptotic effects of proteasome and histone deacetylase inhibitors in prostate cancer cell lines

Kılıçcıoğlu¹,

Konac²,

Varol³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Prostate cancer is one of the most common types of urological cancers. Despite the implementation of effective radiotherapy and chemotherapy methods, prostate cancer cells can still show resistance to treatment. In recent years, a combination of proteasome and histone deacetylase inhibitors has been used to treat various malignancies. In this study, we examined the cytotoxic and apoptotic effects of the proteasome inhibitor bortezomib (Velcade/PS-341) and histone deacetylase inhibitor trichostatin A (TSA), used either alone or in combination, on the human prostate LNCaP and PC3 cell lines. We investigated the cytotoxic activity of these inhibitors using a WST-1 assay, IkBα and caspase-3 mRNA levels by real-time polymerase chain reaction, and caspase-3 activity and activation of phosphorylated (p-IkBα) protein by Western blotting. Low-dose bortezomib and TSA synergistically induced apoptosis in both prostate cancer cell lines. Combination treatment with TSA with bortezomib effectively inactivated NFkB signaling, upregulated the predominant endogenous apoptotic factor caspase-3, and disrupted the NFkB pathway in the androgen-independent PC3 cell line. In contrast, androgen-dependent LNCaP cells showed upregulation of caspase-3 through a pathway other than NFkB. This study examined the possible clinical use of bortezomib and TSA, together with reduced doses of chemotherapeutic agents with high cytotoxicity, to determine their apoptotic effects on the NFkB pathway in prostate cancer cell lines. Therefore, combination bortezomib and TSA treatment may represent a novel therapeutic strategy for prostate cancer.

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“…The therapeutic efficacy of the proteasome inhibitor Bortezomib for treatment of multiple myeloma and mantle cell lymphoma points to the ubiquitin-proteasome system as a promising target for the development of new anticancer strategies (Navon and Ciechanover, 2009;Crawford et al, 2011). As DUBs are key effectors of the ubiquitin-proteasome system, and having in mind their multiple and diverse biological roles, these proteases are emerging as attractive druggable targets in cancer.…”

Section: Targeting Dubs In Cancermentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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Proteasome inhibitors in cancer therapy

Cited by 266 publications

References 78 publications

Melatonin treatment induces apoptosis through regulating the nuclear factor-κB and mitogen-activated protein kinase signaling pathways in human gastric cancer SGC7901 cells

Melatonin treatment induces apoptosis through regulating the nuclear factor-κB and mitogen-activated protein kinase signaling pathways in human gastric cancer SGC7901 cells

Apoptotic effects of proteasome and histone deacetylase inhibitors in prostate cancer cell lines

Deubiquitinases in cancer: new functions and therapeutic options

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