The role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis, and chemoresistance in solid tumors

Grothey, Axel; Voigt, Wieland; Schöber, Christian; Müller, Thomas; Dempke, Wolfram; Schmoll, H.-J.

doi:10.1007/s004320050259

Cited by 77 publications

(54 citation statements)

References 63 publications

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“…Decreased production of IGF-1 by inhibition of GHRH-R by GHRH antagonists occurs in vivo (33). Notably, the IGF-1 signaling axis is dysregulated in various cancers, including prostate cancer (34)(35)(36)(37).…”

Section: Significancementioning

confidence: 99%

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Fahrenholtz

Rick

García

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists-MIA-602, MIA-606, and MIA-690-on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.androgen-independent | G protein-coupled receptor | hypothalamic neurohormone | neuropeptide | targeted therapy

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Section: Significancementioning

confidence: 99%

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Fahrenholtz

Rick

García

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In practice, though, down-regulation of IGF-I activity has been reported to potentiate the apoptotic responsiveness of many cancer cell lines to a range of cytotoxins, including 5-FU, methotrexate, tamoxifen, camptothecin, doxorubicin, etoposide, carboplatin, and ionizing radiation. [245][246][247][248][249][250][251] Analogously, herceptin has been found to boost the responsiveness of ErbB2-overexpressing breast cancer cell lines to paclitaxel and radiotherapy. 252,253 Thus, the published evidence suggests that concurrent antagonism of growth factor signaling is more likely than not to enhance responsiveness to cytotoxic therapy.…”

Section: Multifocal Signal Modulation Therapies As Adjuvants To Cytotmentioning

confidence: 99%

Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

McCarty

Block

2006

Integr Cancer Ther

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NF-κB activity is elevated in a high proportion of cancers, particularly advanced cancers that have been treated previously. Cytotoxic treatment selects for such up-regulation inasmuch as NF-κB promotes transcription of a large number of proteins that inhibit both the intrinsic and extrinsic pathways of apoptosis; NF-κB also boosts expression of mdr1, which expels many drugs from cells. Indeed, high NF-κB activity appears to be largely responsible for the chemo-and radioresistance of many cancers. Thus, agents that suppress NF-κB activity should be useful as adjuvants to cytotoxic cancer therapy. Of the compounds that are known to be NF-κB antagonists, the most practical for current use may be the nonsteroidal anti-inflammatory drugs aspirin, salicylic acid, and sulindac, each of which binds to and inhibits IκB kinase-β, a central mediator of NF-κB activation; the low millimolar plasma concentrations of salicylate required for effective inhibition of this kinase in vivo can be achieved with highdose regimens traditionally used to manage rheumatic disorders. The gastrointestinal toxicity of such regimens could be minimized by using salsalate or enteric-coated sodium salicylate or by administering misoprostol in conjunction with aspirin therapy. Presumably, best results would be seen if these agents were administered for several days prior to a course of chemo-or radiotherapy, continuing throughout the course. This concept should first be tested in nude mice bearing xenografts of chemoresistant human tumors known to have elevated NF-κB activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-κB antagonists and/or agents that target other mediators of down-regulated apoptosis in cancer, such as Stat3; coadministration of salicylate and organic selenium may have intriguing potential in this regard. These strategies may also have potential as adjuvants to metronomic chemotherapy, which seeks to suppress angiogenesis by targeting cycling endothelial cells in tumors.

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“…A comparison of the levels of phospho-Akt and phospho-Erk using tissue lysate between before and after IGF neutralization may support our conclusion. Conversely, it is possible that the IGF-neutralizing strategy can enhance the effects of chemotherapy (44) and radiation therapy (45) by potentiating the apoptosis induced by these treatments.…”

Section: Neutralization Of Paracrine Igfs Suppresses the Liver Metastmentioning

confidence: 99%

Blockade of Paracrine Supply of Insulin-Like Growth Factors Using Neutralizing Antibodies Suppresses the Liver Metastasis of Human Colorectal Cancers

Miyamoto

Nakamura

Shitara

et al. 2005

Clinical Cancer Research

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Environmental stimuli, such as organ-specific growth factors, can influence the metastatic potential of a tumor. The liver is the main source of insulin-like growth factors (IGFs). The importance of IGF signal in hepatic metastasis has been clarified mainly by IGF-I receptor targeting strategies. This study aims to confirm these precedent reports by novel tool, neutralizing antibodies against IGFs and to show that IGFs are promising therapeutic targets for hepatic metastasis in vivo. Hepatic metastasis was induced by intrasplenic injection of human colorectal cancer cell line, HT29. The antimetastatic effects of three antibodies (anti-mouse IGF-I, anti-mouse IGF-II, and anti-human/mouse IGF-II designated KM1468) were tested singly or in combination in the early phase of metastasis. The dose escalation effect of KM1468 and its survival benefit were examined in the early and late phases of metastasis. The mechanism of IGF neutralization was investigated with immunohistochemistry. Dual neutralization of paracrine IGF-I and IGF-II showed modest additive antimetastatic effects than single neutralization of IGF-I or IGF-II. In any phase of metastasis, neutralization led to significant tumor growth inhibition and longer survival. Dose escalation of KM1468 influenced survival only in the late phase of metastasis. Apoptosis increased significantly in the antibody-treated group compared with the control group (P = 0.0025) In conclusion, IGFs are promising therapeutic targets for hepatic metastases of colorectal cancers. However, the IGF dependency is probably variable in the metastatic process.Almost one-third of patients dying from colorectal cancer have metastatic tumors only in the liver. The control of hepatic metastasis leads directly to an improvement in the overall cure rate for colorectal cancer (1). However, our lack of understanding of the molecular mechanisms mediating the process of hepatic metastasis means that few theoretical treatments for this syndrome have yet been developed.The insulin-like growth factors (IGFs) have been widely investigated for a possible role in promoting the oncogenic transformation, growth, and survival of cancer cells (2 -6). They are expressed ubiquitously and act as endocrine, paracrine, and autocrine growth factors. In most tissues, they are synthesized together with six molecular species of specific binding proteins (IGFBP-1 to IGFBP-6), which modulate IGF action in the cell environment, generally by inhibiting it. Limited proteolysis of IGFBPs is an essential mechanism in the regulation of IGF bioavailability both in the bloodstream and at the cellular level (7,8). The liver is the main source of IGFs, and there are reports demonstrating the importance of IGF signals in hepatic metastasis formation (9 -13). We speculated in a previous report that free/bioactive IGFs generated from IGFBP-3 proteolysis by matrix metalloproteinase-7 play a crucial role in hepatic metastasis in human colorectal cancers (14).Recently, this IGF system has been recognized as a potent therapeu...

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The role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis, and chemoresistance in solid tumors

Cited by 77 publications

References 63 publications

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

Blockade of Paracrine Supply of Insulin-Like Growth Factors Using Neutralizing Antibodies Suppresses the Liver Metastasis of Human Colorectal Cancers

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