Novel combination therapy against metastatic and androgen‐independent prostate cancer by using gefitinib, tamoxifen and etoposide

Mimeault, Murielle; Venkatraman, Ganesh; Johansson, Sonny L.; Moore, Erik; Henichart, J. P.; Depreux, Patrick; Lin, Ming Fong; Batra, Surinder K.

doi:10.1002/ijc.22268

Cited by 27 publications

(49 citation statements)

References 54 publications

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“…Previous studies have demonstrated that with the disease progresses to more advanced stages, TGF-α is the predominant ligand for EGFR (33,34). Moreover, cell lines derived from different prostatic cancers and their metastases, including DU145 overexpress TGF-α (35,36), and TGF-α/EGFR autocrine loop is a hallmark of PCa invasion and progression (37,38). Therefore, based on these studies and our results, we concluded that ADAM17 contributes to PCa cell invasion through activation of EGFR pathway by shedding of pro-TGF-α.…”

Section: Discussionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

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Abstract. ADAM17, also known as tumor necrosis factor-α converting enzyme (TACE), is involved in proteolytic ectodomain shedding of cell surface molecules and cytokines. Although aberrant expression of ADAM17 has been shown in various malignancies, the function of ADAM17 in prostate cancer has not been clarified. In the present study, we sought to elucidate whether ADAM17 contributes to prostate cancer cell invasion, as well as the mechanism involved in the process. The expression pattern of ADAM17 was investigated in human prostate cancer cells. The results showed that ADAM17 expression levels are correlated with the invasive ability of androgen-independent prostate cancer cell lines. Further, ADAM17 was overexpressed in cells showing high invasion characteristics, activation of the EGFR-MEK-ERK pathway, up-regulation of MMP-2, MMP-9, and an increased TGF-α release into the supernatant. However, AG1478, PD98059 and antibody against TGF-α deactivating the EGFR-MEK-ERK signaling pathway, abolished up-regulation of MMP-2, MMP-9 and prevented cell invasion. In addition, cells with knockdown of ADAM17 by siRNA exhibited low invasive ability, deactivated EGFR-MEK-ERK signaling pathway, reduced TGF-α released and down-regulation of MMP-2, MMP-9. However, these effects could be reversed by simultaneous addition of TGF-α. These data demonstrated that ADAM17 contributes to androgen-independent prostate cancer cell invasion by shedding of EGFR ligand TGF-α, which subsequently activates the EGFR-MEK-ERK signaling pathway, leading finally to overexpression of MMP-2 and MMP-9. This study suggests that the ADAM17 expression level may be a new predictive biomarker of invasion and metastasis of prostate cancer, and ADAM17 could provide a target for treating metastatic PCa. IntroductionProstate cancer (PCa) is one of the most common malignancies among Western males with an occurrence of approximately 192,280 new cases and 27,360 deaths in the US, in 2009 (1). The growth and maintenance of cancerous cells in the early stages of prostate cancer is androgen-dependent and therapy often involves androgen deprivation (2). In the later stages therapeutic alternatives are not available, as the tumor progresses from androgen-dependence to -independence. The lack of effective therapies for advanced PCa is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Therefore, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of PCa (4).The ADAMs (a disintegrin and metalloproteinase) are members of the metzincin superfamily of Zn-dependent matrix metalloproteinases. They are transmembrane and secreted proteins with important roles in diverse biological functions, such as fertilization, adhesion, migration, proteolysis and signaling (5,6). Recent...

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Section: Discussionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

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“…Immunohistochemistry Immunohistochemical studies on the localization of SHH in normal and malignant prostate tissues were done as described previously (31). Briefly, the immunostaining was carried out on 32 pairs of AccuMax array tissue sections (Petagen, Inc., Shinchon-dong, Seoul, Korea) from patients with primary prostatic adenocarcinoma (Gleason scores 4 -10) with their corresponding normal adjacent tissues from the same patients.…”

Section: Methodsmentioning

confidence: 99%

“…Western Blot Analyses Prostate cancer cells were maintained in medium containing 10% fetal bovine serum for 48 h, and the conditioned medium (supernatants) was harvested and cells were extracted in lysis buffer as described previously (22,31). The expression levels of SHH precursor and its NH 2 -terminal product SHH-N were estimated by Western blot in conditioned medium, and lysate samples prepared from prostate cancer cells by using rabbit polyclonal anti-SHH antibody.…”

Section: Confocal Microscopymentioning

confidence: 99%

“…Moreover, it has also been reported that the induction of de novo synthesis of the sphingolipid ceramide through the activation of enzyme ceramide synthase by diverse agents, such as activator of protein kinase Ca, 12-O-tetradecanoylphorbol 13-acetate, and anandamide, or the inhibition of acid ceramidase by using ceramide analogue, B13, induces apoptosis in metastatic prostate cancer cells in vitro and enhances their sensitivity to radiation-induced apoptosis in vivo (28 -30). Of therapeutic interest, our recent works have also indicated that the use of lower doses of selective EGFR inhibitor, gefitinib or PD153035, alone or in combination with other cytotoxic agents, acting as activators of caspase and/or ceramide accumulation, including cyclopamine, protein kinase A inhibitor (Rp-cAMPs), sodium nitroprusside, tamoxifen, and/or etoposide, induced a growth arrest and apoptosis of diverse metastatic prostate cancer cells more effectively than the individual drugs (2,19,20,22,31).…”

Section: Introductionmentioning

confidence: 99%

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Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells

Mimeault

Johansson²,

Vankatraman

et al. 2007

Molecular Cancer Therapeutics

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The epidermal growth factor receptor (EGFR) and hedgehog cascades provide a critical role in prostate cancer progression and contribute to the resistance to clinical therapies and disease relapse. Therefore, we evaluated, for the first time, the antiproliferative and cytotoxic effects induced by a combination of selective inhibitors of EGFR tyrosine kinase and smoothened hedgehog signaling element, gefitinib and cyclopamine, with a current chemotherapeutic drug used in the clinics, docetaxel, on some metastatic prostate cancer cell lines. Immunohistochemical analyses revealed that sonic hedgehog (SHH) expression was enhanced in 39% of primary prostatic adenocarcinomas (Gleason scores 4 -10) compared with the corresponding normal tissues of the same prostate gland from 32 prostate cancer patients. The confocal microscopy and Western blot analyses have also indicated the high expression levels of SHH and EGFR in metastatic LNCaP, DU145, and PC3 cells. Moreover, the results revealed that the drugs, alone or in combination, at lower concentrations inhibited the growth of EGF plus SHH -stimulated and serum-stimulated androgenresponsive LNCaP-C33 and androgen-independent LNCaP-C81, DU145, and PC3 cells. Importantly, the combined docetaxel, gefitinib, and cyclopamine also caused a higher rate of apoptotic death of prostate cancer cells compared with individual agents. The cytotoxic effects induced by these drugs in PC3 cells seem to be mediated in part through the cellular ceramide production and activation of caspase cascades via a mitochondrial pathway and the release of cytochrome c into the cytosol. Additionally, the combined agents were more effective at suppressing the invasiveness of PC3 cells through Matrigel in vitro than the single drugs. These findings indicate that the combined use of inhibitors of EGF-EGFR and hedgehog signaling with docetaxel could represent a more promising strategy for treatment in patients with metastatic and androgen-independent prostate cancer. [Mol Cancer Ther 2007;6(3):967-78]

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“…It has been shown that the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, hyaluronan (HA)/CD44, transforming growth factor (TGF)-β/ TGF-βR receptors and stromal cell-derived factor-1 (SDF-1)/ CXC chemokine receptor 4 (CXCR4) frequently occurs during PC progression to locally invasive and metastatic CRPCs (5,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). These tumorigenic cascades can account for the sustained growth, survival, invasion, metastases and treatment resistance of PC cells.…”

Section: Introductionmentioning

confidence: 99%

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

Mimeault

Batra

2011

Mol Med

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Recent gene expression profiling analyses and gain-and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC-and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.

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Novel combination therapy against metastatic and androgen‐independent prostate cancer by using gefitinib, tamoxifen and etoposide

Cited by 27 publications

References 54 publications

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

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