Therapeutic Potential of Clusterin Inhibition in Human Cancer.

Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this article, we present the existing knowledge to date on the inhibition of this protein in different types of cancer and analyze the importance it could have in the development of new therapies targeted against this disease.

N-cadherin upregulation mediates adaptive radioresistance in glioblastoma.

Glioblastoma (GBM) is composed of heterogeneous tumor cell populations, including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance in GBM, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by a reduction in cell proliferation and an increase in cell-cell adhesion and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of ß-catenin at the cell surface, which suppressed Wnt/ß-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin, a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation.

Clusterin as modulator of carcinogenesis: A potential avenue for targeted cancer therapy.

Clusterin (CLU) is an evolutionary conserved molecular chaperone present in different human tissues and fluids and established to be a significant cancer regulator. It controls several cancer-associated cellular events, including cancer cell proliferation, stemness, survival, metastasis, epithelial-mesenchymal transition, therapy resistance, and inhibition of programmed cell death to support cancer growth and recurrence. This multifunctional role of CLU makes it an ideal target for cancer control. More importantly, genetic and antisense-mediated (OGX-011) inhibition of CLU enhances the anticancer potential of different FDA-approved chemotherapeutic drugs at the clinical level, improving patient's survival. In this review, we have discussed the detailed mechanism of CLU-mediated modulation of different cancer-associated signaling pathways. We have also provided updated information on the current preclinical and clinical findings that drive trials in various cancer types for potential targeted cancer therapy.

Liposomal co-delivery-based quantitative evaluation of chemosensitivity enhancement in breast cancer stem cells by knockdown of GRP78/CLU.

Resistance to chemotherapy is a key factor in the inefficacy of various forms of treatments for cancer. In the present study, chemo-resistant proteins, including glucose-regulated protein 78 (GRP78)/clusterin (CLU) targeted 1,2-dioleoyloxy-3-trimethylammoniumpropane (DOTAP) liposomes, were developed as a delivery system for co-delivery of camptothecin (CPT) and GRP78 siRNA/CLU siRNA. Their drug/gene co-deliveries were quantitatively assessed in cancer stem cells (CSC) and MCF-7 cells. DOTAP-CPT/siRNA were prepared via electrostatic interaction on GRP78 siRNA or CLU siRNA. The size and ζ-potential of liposomes and lipoplexes were measured by dynamic light scattering techniques and electrophoretic light scattering spectrophotometry. The lipoplexes formation was tested by using gel electrophoresis. Immunofluorescence analysis showed that the expression level of CLU and GRP78 were significantly elevated in CSC compared to MCF-7 cells. Transfection and drug-delivery efficiency of DOTAP-CPT/siRNA were quantitatively compared with Lipofectamine 2000. Compared to free CPT, DOTAP-CPT-siCLU delivery in CSC and MCF-7 cells increased transfection efficiency and chemo-sensitivity by 4.1- and 5.9-fold, respectively. On the other hand, DOTAP-CPT-siGRP78 delivery increased transfection efficiency and chemo sensitivity by 4.4- and 6.2-fold in CSC and MCF-7 cells, respectively, compared to free CPT. It is significant that 3 ± 1.2-fold increase in transfection efficiency was achieved by lipofectamine. Consequently, an increase in anti-cancer/gene silencing efficacy was quantitatively observed as an effect of DOTAP-CPT/siRNA treatment, which was relatively higher than lipofectamine treatment. Conclusively, our experimental data quantitatively demonstrate that using DOTAP-CPT-siRNA specifically targeting (CSCs) chemo-resistant protein in vitro offers substantial potential for synergistic anti-cancer therapy.

Clusterin inhibition mediates sensitivity to chemotherapy and radiotherapy in human cancer.

Since its discovery in 1983, the protein clusterin (CLU) has been isolated from almost all human tissues and fluids and linked to the development of different physiopathological processes, including carcinogenesis and tumor progression. During the last few years, several studies have shown the cytoprotective role of secretory CLU in tumor cells, inhibiting their apoptosis and enhancing their resistance to conventional treatments including hormone depletion, chemotherapy, and radiotherapy. In an effort to determine the therapeutic potential that the inhibition of this protein could have on the development of new strategies for cancer treatment, numerous studies have been carried out in this field, with results, in most cases, satisfactory but sometimes contradictory. In this document, we summarize for the first time the current knowledge of the effects that CLU inhibition has on sensitizing tumor cells to conventional cancer treatments and discuss its importance in the development of new strategies against cancer.

The Role of Clusterin in Carcinogenesis and its Potential Utility as Therapeutic Target.

Clusterin is a glycoprotein that has been implicated in many processes, including apoptosis, cell cycle regulation and DNA repair. Since clusterin expression has also been associated with tumorigenesis and the progression of various malignancies including prevalent tumors like prostate, colon, bladder and breast, this protein has been proposed as a good candidate for future treatments. There have been numerous studies conducted in cell lines and xenograft models with successful results that, in general, justify the use of clusterin as a therapeutic target. However, it is still necessary to continue with these studies in order to achieve a better understanding of the role of this protein in carcinogenesis and to determine those specific situations in which its therapeutic use may be more favorable. In this review, we will make a brief description of clusterin structure and genetics, its implication in tumorigenesis and cancer progression and its prognosis utility. Finally, we will analyze the effects of clusterin inhibition in different types of cancer.

Lentivirus-mediated shRNA interference of clusterin blocks proliferation, motility, invasion and cell cycle in the ovarian cancer cells.

BACKGROUND: In a previous analysis on the patients with ovarian cancers, we have found that clusterin is a biomarker associated with ovarian cancer in vivo and may be a prognostic factor associated with adverse outcome. Here, we explored the effect of lentivirus-mediated shRNA interference of clusterin, investigated whether clusterin was associated with adverse outcome of ovarian cancer cells in vitro. METHODS: OVCAR-3 and TOV-21G cell lines were infected with the lentivirus for delivering clusterin shRNA, and the stably transfected cells were selected. The effect of clusterin silencing was detected by western blotting assay. The proliferation, clonability, migration, invasion and cell cycle of two cell lines were detected separately by MTT assay, clone formation assay, scratch assay, transwell assay and fluorescence-activated cell sorting. RESULTS: Following clusterin silencing with shRNA, the expression of clusterin in two cell lines were decreased. And the proliferation, clonability, migration, invasion of these two cell lines were down-regulated apparently. The cell cycle of two cell lines was disturbed, cells in G1 phase was increased, but cells in G2 and S phase was decreased. CONCLUSIONS: The expression of clusterin is significantly correlated with the biological characteristics of ovarian cancer cells, it may be a potential molecular for ovarian cancer treatment.

sCLU regulates cisplatin chemosensitivity of lung cancer cells in vivo.

BACKGROUND: In a previous analysis using a lung cancer cell line model, we have found that therapies directed against secreted clusterin (sCLU) and its downstream signaling targets pAkt and pERK1/2 may have the potential to enhance the efficacy of cisplatin (DDP)-based chemotherapy in vitro. Here, we investigated the therapies directed against sCLU on the DDP-based chemotherapy in vivo and explored the mechanism. METHODS: Using lung cancer cell lines, A549 cells and DDP-resistant A549 cells (A549(DDP)), we determined the effect of sCLU silencing using short interfering double-stranded RNA (siRNA) on chemosensitivity in immunocompromised mice bearing A549(DDP) tumors. We then determined the effect of sCLU overexpression via stable sCLU transfection on chemosensitivity in immunocompromised mice bearing A549 tumors. The effect of sCLU silencing or overexpression on pAkt and pERK1/2 expression and chemosensitivity in vivo was detected by Western blot assay. RESULTS: The results showed sCLU silencing increased the chemosensitivity of A549(DDP) cells to DDP in vivo via downregulation of pAkt and pERK1/2 expression. And sCLU overexpression decreased the chemosensitivity of A549 cells to DDP in vivo via upregulation of pAkt and pERK1/2 expression. CONCLUSIONS: We therefore concluded that the DDP-induced sCLU activation, which involved induction of pAkt and pERK1/2 activation that confer DDP resistance in immunocompromised mice and alteration of this balance, allows sensitization to the antitumor activity of cisplatin chemotherapy.

Clusterin/apolipoprotein J binds to aggregated LDL in human plasma and plays a protective role against LDL aggregation.

Clusterin/apolipoprotein J (apoJ) is an extracellular chaperone involved in the quality control system against protein aggregation. A minor part of apoJ is transported in blood bound to LDLs, but its function is unknown. Our aim was to determine the role of apoJ bound to LDLs. Total LDL from human plasma was fractionated into native LDL [LDL(+)] and electronegative LDL [LDL(-)]. The latter was separated into nonaggregated [nagLDL(-)] and aggregated LDL(-) [agLDL(-)]. The content of apoJ was 6-fold higher in LDL(-) than in LDL(+) and 7-fold higher in agLDL(-) than in nagLDL(-). The proportion of LDL particles containing apoJ (LDL/J+) was 3-fold lower in LDL(+) than in LDL(-). LDL/J+ particles shared several characteristics with agLDL(-), including increased negative charge and aggregation. apoJ-depleted particles (LDL/J-) showed increased susceptibility to aggregation, whether spontaneous or induced by proteolysis or lipolysis, as was revealed by turbidimetric analysis, gel filtration chromatography, lipoprotein precipitation, native gradient gel electrophoresis, circular dichroism, and transmission electronic microscopy. The addition of purified apoJ to total LDL also prevented its aggregation induced by proteolysis or lipolysis. These findings point to apoJ as a key modulator of LDL aggregation and reveal a putative new therapeutic strategy against atherosclerosis.

Silencing clusterin gene transcription on effects of multidrug resistance reversing of human hepatoma HepG2/ADM cells.

Abnormal clusterin (CLU) expression is associated with multidrug resistance (MDR) of hepatocellular carcinoma (HCC). In the present study, the CLU expression was analyzed in human hepatoma cells and chemoresistant counterpart HepG2/ADM cells. Compared with L02 cells, the overexpression of cellular CLU was identified in HepG2, HepG2/ADM, SMMC7721, Hep3B ,and PLC cells and relatively lower expression in Bel-7404, SNU-739, and MHCC97H cells. Specific short hairpin RNAs (shRNAs) to silence CLU gene transcription were designed, and the most effective sequences were screened. After the HepG2/ADM cells transfected with shRNA-1, the inhibition of CLU expression was 73.68 % at messenger RNA (mRNA) level by real-time quantitative RT-PCR with obvious enhancement in cell chemosensitivity, increasing apoptosis induced by doxorubicin using fluorescence kit, and Rh-123 retention qualified with flow cytometry. Knockdown CLU also significantly decreased the drug efflux pump activity through the depression of MDR1/P-glycoprotein (q = 11.739, P < 0.001). Moreover, silencing CLU led to downregulation of ß-catenin (q = 13.544, P = 0.001), suggesting that downregulation of CLU might be a key point to reverse multidrug resistance of HepG2/ADM cells.

Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival.

We define stress-induced adaptive survival pathways linking autophagy with the molecular chaperone clusterin (CLU) that function to promote anticancer treatment resistance. During treatment stress, CLU co-localizes with LC3 via an LIR-binding sequence within autophagosome membranes, functioning to facilitate LC3-Atg3 heterocomplex stability and LC3 lipidation, and thereby enhance autophagosome biogenesis and autophagy activation. Stress-induced autophagy is attenuated with CLU silencing in CLU(-/-) mice and human prostate cancer cells. CLU-enhanced cell survival occurs via autophagy-dependent pathways, and is reduced following autophagy inhibition. Combining CLU inhibition with anticancer treatments attenuates autophagy activation, increases apoptosis and reduces prostate cancer growth. This study defines a novel adaptor protein function for CLU under stress conditions, and highlights how co-targeting CLU and autophagy can amplify proteotoxic stress to delay cancer progression.

Secreted clusterin (sCLU) regulates cell proliferation and chemosensitivity to cisplatin by modulating ERK1/2 signals in human osteosarcoma cells.

BACKGROUND: Several studies have shown that secreted clusterin (sCLU) up-regulation in multi-drug resistant osteosarcoma (OS) cells relates to enhanced drug resistance. Furthermore, sCLU silencing directed against sCLU induces significant reduction of cellular growth and sensitizes OS cells to chemotherapy. However, the molecular mechanisms underlying the effect of sCLU on OS cells are not known. METHODS: To evaluate the roles and possible mechanisms of sCLU in chemoresistance of OS cells to cisplatin (DPP), we utilized RNA interference to knockdown sCLU expression in the sCLU-rich U-2 OS cells and to overexpress sCLU in the sCLU-poorer KH OS cells, and further assessed the cell viability and chemosensitivity to DDP as well as possible signaling transduction pathways. RESULTS: The data showed that sCLU depletion inhibited growth and sensitized sCLU-rich U-2 OS cells to cisplatin in vitro and in vivo by inducing inactivation of ERK1/2, and sCLU overexpression promoted growth and increased resistance of sCLU-less KH OS cells to cisplatin in vitro and in vivo by activation of ERK1/2. CONCLUSIONS: The data also suggests critical roles of sCLU in OS cell chemoresistance to DPP and raises the possibility of sCLU depletion as a promising approach to OS therapy.

Emerging targets to monitor and overcome docetaxel resistance in castration resistant prostate cancer (review).

Drug development for castration resistant prostate cancer (CRPC) is challenging, since this cancer is still associated with high mortality and limited therapeutic options. In 2004, docetaxel became the first-line chemotherapy for CRPC improving survival by a few months and remains the standard of care in CRPC patients. However, existing or developing resistance to docetaxel in patients is the main limitation of its efficacy. The present review presents the molecular mechanisms involved in docetaxel toxicity and in docetaxel resistance in prostate cancer cells. We outlined the endogenous mechanisms of resistance and the role of tumor microenvironment in the resistance of CRPC to docetaxel. This has led us to focus on molecules associated with resistance, such as the molecular chaperones heat shock proteins (HSPs) and clusterin (CLU), and the cytokines interleukin-6 (IL-6) and the divergent member of the tumor growth factor family MIC-1 (macrophage inhibitory cytokine-1 also named GDF-15). We discuss their interest as blood-based markers to monitor docetaxel resistance. Finally, new therapies intended to overcome docetaxel resistance of CRPC targeted on these molecular resistance pathways are present.

Secreted clusterin gene silencing enhances chemosensitivity of a549 cells to cisplatin through AKT and ERK1/2 pathways in vitro.

BACKGROUND/AIMS: Several studies have shown secreted clusterin (sCLU) silencing directed against sCLU mRNA in sCLU-rich lung cancer cell lines sensitized cells to chemotherapy. However, the molecular mechanisms underlying the effect of sCLU silencing on lung cancer cell chemosensitivity is not known. In the present study, we aimed to determine that vector expressing short hairpin RNA against sCLU RNA (sCLU-shRNA) enhances the chemosensitivity in human small cell lung cancer A549 cells in vitro by inhibition of phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt). METHODS: The pCDNA3.1-sCLU and control scrambled pCDNA3.1 plasmid was constructed. We investigated the effects of sCLU overexpression by pCDNA3.1-sCLU transfection on chemosensitivity to cisplatin (DDP) in A549 cells in vitro. We down-regulated sCLU expression by short hairpin RNA against sCLU RNA (sCLU-shRNA) and investigated the effects on chemosensitivity to DDP in A549 cells and A549(DDP)in vitro. In order to confirm the correlation between sCLU and AKT and ERK1/2 signals, cells were treated with wortmannin and U0126. RESULTS: We found the chemotherapeutic agent DDP activated sCLU. Overexpression of sCLU increased cellular DDP chemoresistance in the A549(DDP) and pCDNA3. 1-sCLU transfected A549 cells via inhibition DDP-induced apoptosis. Whereas sCLU knockdown induced chemosensitization in the S549 and A549(DDP) cells via increase of DDP-induced apoptosis. sCLU overexpression activated pAKT Ser(473) and pERK1/2(Thr202/Tyr204), and vice versa. Inhibition of pAKT Ser(473) and pERK1/2(Thr202/Tyr204) was sufficient to induce significant recover y in chemosensitivity to DDP in A549(DDP) in the presence of sCLU overexpression. The DDP activated sCLU, which directly regulated pAKT and pERK1/2. CONCLUSIONS: This novel finding suggests that therapies directed against sCLU and its downstream signaling targets pAKT and pERK1/2 may have the potential to enhance the efficacy of DDP-based chemotherapy.

Clusterin silencing inhibits proliferation and reduces invasion in human laryngeal squamous carcinoma cells.

BACKGROUND: Clusterin is, in its major form, a secreted heterodimeric disulfide-linked glycoprotein (sCLU), which plays important roles in cell survival and death. In laryngeal squamous cell carcinomas (LSCC), sCLU is up-regulated and its expression is related to the invasiveness of these tumors. The purpose of this study was to explore the inhibiting role of sCLU gene silence in the invasive ability and growth of Hep-2 human laryngeal squamous carcinoma cells (Hep-2) by transfection of short hairpin RNA expression plasmids against sCLU (sCLU-shRNA) (in vivo) or small interference RNA (sCLU-siRNA) (in vitro). METHODS: sCLU-siRNA and the control siRNA were transfected into Hep-2 cells using Lipofectamine 2000. RT-PCR and Western blot were used to detect the effect of siRNA transfection on sCLU mRNA and sCLU protein expression. The invasive activity of sCLU-siRNA-transfected Hep-2 cells was measured with the modified Boyden chamber assay and wound healing assay. The effects of sCLU-siRNA on cell proliferation were evaluated by MTT assay. Apoptosis was measured by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double-staining methods. We next evaluated the effects of sCLU silencing by sCLU-shRNA transfection in vivo on tumor growth and metastatic properties to the lung. Terminal deoxytransferase-mediated dUTP nick end labeling (TUNEL) staining was used to observe the apoptosis in the xenografts. RESULTS: It showed that siRNA-mediated down-regulation of sCLU expression in Hep-2 cells significantly inhibited cell proliferation and promoted apoptosis in vitro. Furthermore, siRNA-mediated down-regulation of sCLU expression decreases in vitro cell migration and invasion ability. In vivo, the average volume of tumors in the sCLU-shRNA transfected group was significantly lower than in the control group (P<0.01), and the significant apoptosis detected with TUNEL was indicated in the sCLU-shRNA transfected groups (P<0.05). Significantly, we found that sCLU-shRNA could exert marked inhibition of the lung metastasis of Hep-2 cells in nude mice in vivo. CONCLUSIONS: sCLU gene silence can inhibit invasion and growth of LSCC. sCLU may provide a potential therapeutic target against human LSCC.

Heat shock and other apoptosis-related proteins as therapeutic targets in prostate cancer.

Defects within apoptotic pathways have been implicated in prostate cancer (PCa) tumorigenesis, metastatic progression and treatment resistance. A hallmark of cancers is the ability to derail apoptosis by inhibiting the apoptotic signal, reducing the expression of apoptotic proteins and/or amplifying survival signals through increased production of antiapoptotic molecule. This review describes associations between heat shock proteins (HSPs) and the human androgen receptor (AR), the role of HSPs and other stress-induced proteins in PCa development and emerging strategies in targeting these protective proteins to treat PCa.

Insulin-like growth factor-I induces CLU expression through Twist1 to promote prostate cancer growth.

Clusterin (CLU) is cytoprotective molecular chaperone that is highly expressed in castrate-resistant prostate cancer (CRPC). CRPC is also characterized by increased insulin-like growth factor (IGF)-I responsiveness which induces prostate cancer survival and CLU expression. However, how IGF-I induces CLU expression and whether CLU is required for IGF-mediated growth signaling remain unknown. Here we show that IGF-I induced CLU via STAT3-Twist1 signaling pathway. In response to IGF-I, STAT3 was phosphorylated, translocated to the nucleus and bound to the Twist1 promoter to activate Twist1 transcription. In turn, Twist1 bound to E-boxes on the CLU promoter and activated CLU transcription. Inversely, we demonstrated that knocking down Twist1 abrogated IGF-I induced CLU expression, indicating that Twist1 mediated IGF-I-induced CLU expression. When PTEN knockout mice were crossed with lit/lit mice, the resultant IGF-I deficiency suppressed Twist1 as well as CLU gene expression in mouse prostate glands. Moreover, both Twist1 and CLU knockdown suppressed prostate cancer growth accelerated by IGF-I, suggesting the relevance of this signaling not only in an in vitro, but also in an in vivo. Collectively, this study indicates that IGF-I induces CLU expression through sequential activation of STAT3 and Twist1, and suggests that this signaling cascade plays a critical role in prostate cancer pathogenesis.

Custirsen (OGX-011): clusterin inhibitor in metastatic prostate cancer.

Adenocarcinoma of the prostate is the most common cancer in men in the Western Hemisphere. This diagnosis includes a clinicopathologically diverse collection of disease entities, encompassing a spectrum from early localized disease to advanced-stage castration-sensitive and ultimately metastatic, castration-resistant states. Although early-stage disease is treatable and potentially curable, treatment options for castration-resistant prostate cancer, the common pathway to prostate cancer death, remain limited and palliative in nature. Therapeutic resistance to androgen blockade, cytotoxic chemotherapy, and radiotherapy is underpinned by a number of cellular mechanisms. The upregulation of protective, antiapoptotic chaperone proteins is one of these mechanisms, and is exemplified by the protein clusterin in castration-resistant prostate cancer. Antisense oligonucleotide technology provides the potential to inhibit specific genes in cancer cells and with this the possibility of a vast impact in oncology, but no antisense drugs have been approved for use in cancer patients to date. Custirsen (OGX-011) is a novel antisense oligonucleotide drug which targets clusterin expression, and its application in prostate cancer is reviewed in this article.

Clusterin confers resistance to TNF-alpha-induced apoptosis in breast cancer cells through NF-kappaB activation and Bcl-2 overexpression.

Secretory clusterin (sClu) is an anti-apoptotic protein that plays a role in protecting cells from Tumour-necrosis factor (TNF)-alpha-induced apoptosis. The aim of the present study was to investigate the molecular mechanisms underlying the effect of sClu on TNF-alpha-induced apoptosis in breast cancer cells. The wild-type p53 expressing MCF-7 cell line was engineered to overexpress sClu (MCF-7/sClu), whereas the MDA-MB-231 cell line with mutant p53 was transfected with a sClu silencing siRNA (MDA-MB-231/sClu siRNA). The effects of clusterin overexpression and downregulation on apoptosis and sensitivity to TNF-alpha were examined in vitro. Our results showed that TNF-alpha treatment increased Bcl-2 mRNA and protein levels in breast cancer cells, suggesting that Bcl-2 is directly regulated by nuclear factor-kappaB (NF-kappaB) in response to TNF-alpha. The induction of Bcl-2 was mediated by the p65 subunit of NF-kappaB. siRNA-mediated silencing of Bcl-2 led to a significant increase in TNF-alpha-induced apoptosis. Silencing of sClu in MDA-MB-231/sClu siRNA cells abrogated TNF-alpha-mediated NF-kappaB activation and Bcl-2 overexpression, and rendered the MDA-MB-231/sClu siRNA cells significantly more sensitive to TNF-alpha-mediated apoptosis than the parental cells. Furthermore, overexpression of sClu in MCF-7/sClu cells promoted TNF-alpha-mediated NF-kappaB activity and Bcl-2 overexpression, and rendered the MCF-7/Clu cells significantly more resistant to TNF-alpha-mediated apoptosis. Inhibition of NF-kappaB activity or p65 and Bcl-2 expression reversed these effects. The present results suggested that sClu confers breast cancer cells resistance to TNF-alpha-induced apoptosis through NF-kappaB activation and Bcl-2 overexpression.

Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin in development for the treatment of prostate cancer.

Clusterin is a stress-induced cytoprotective chaperone that confers broad-spectrum treatment resistance and is overexpressed across a number of cancers. custirsen (OGX-011) is a promising novel second-generation antisense inhibitor of clusterin in clinical development. This article describes the mechanism of action and safety profile of OGX-011 and details the Phase I and II results in human solid organ malignancies. Two Phase III registration trials are currently under recruitment evaluating OGX-011 in combination with chemotherapy in patients with metastatic castration-resistant prostate cancer. These studies not only have the potential to significantly alter the standard of care in prostate cancer, but would also endorse a new class of targets and targeted therapy approach for cancer.