Potentiating effects of GHRH analogs on the response to chemotherapy

Perez, Roberto; Block, Norman L.; Rick, Ferenc G.

doi:10.1080/15384101.2015.1010893

Cited by 12 publications

(10 citation statements)

References 56 publications

(72 reference statements)

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“…In vivo, the treatment with the GHRH agonist JI34 in combination with doxorubicin suppressed the growth of U-87 MG glioblastoma xenografted into nude mice more powerfully than doxorubicin alone (42). The differentiation of cancer stem cells by GHRH agonist was suggested as a possible mechanism of action (42,43). In the present study, we found a down-regulation of GHRH-Rs in the pituitary and tumors of animals after sustained in vivo treatment with the synthetic GHRH agonist MR409 concomitantly with the reduction in tumor size of the three types of lung cancers.…”

Section: Discussionmentioning

confidence: 99%

Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

Wang

Cai

et al. 2018

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

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The effects of the growth hormone-releasing hormone (GHRH) agonist MR409 on various human cancer cells were investigated. In H446 small cell lung cancer (SCLC) and HCC827 and H460 (non-SCLC) cells, MR409 promoted cell viability, reduced cell apoptosis, and induced the production of cellular cAMP in vitro. Western blot analyses showed that treatment of cancer cells with MR409 up-regulated the expression of cyclins D1 and D2 and cyclin-dependent kinases 4 and 6, down-regulated p27kip1, and significantly increased the expression of the pituitary-type GHRH receptor (pGHRH-R) and its splice-variant (SV1). Hence, in vitro MR409 exerts agonistic action on lung cancer cells in contrast to GHRH antagonists. However, in vivo, MR409 inhibited growth of lung cancers xenografted into nude mice. MR409 given s.c. at 5 μg/day for 4 to 8 weeks significantly suppressed growth of HCC827, H460, and H446 tumors by 48.2%, 48.7%, and 65.6%, respectively. This inhibition of tumor growth by MR409 was accompanied by the down-regulation of the expression of pGHRH-R and SV1 in the pituitary gland and tumors. Tumor inhibitory effects of MR409 in vivo were also observed in other human cancers, including gastric, pancreatic, urothelial, prostatic, mammary, and colorectal. This inhibition of tumor growth parallel to the down-regulation of GHRH-Rs is similar and comparable to the suppression of sex hormone-dependent cancers after the down-regulation of receptors for luteinizing hormone-releasing hormone (LHRH) by LHRH agonists. Further oncological investigations with GHRH agonists are needed to elucidate the underlying mechanisms.

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Section: Discussionmentioning

confidence: 99%

Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

Wang

Cai

et al. 2018

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

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“…Preclinical studies using nude mice models with human cancer cell lines suggest that antagonistic analogs of GHRH do not only directly inhibit proliferation in cancers of different types but also potentiate the effects of cytotoxic chemotherapies [35]. Treatment with a GHRH antagonist showed a tumor reducing potential comparable to conventional chemotherapy with minimal side effects in xenograft transplanted nude mice models using non-apocrine human TNBC cell lines [29,30].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The expression of GHRH and its receptors in breast carcinomas with apocrine differentiation—further evidence of the presence of a GHRH pathway in these tumors

et al. 2017

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Apocrine breast carcinomas were evaluated for the expression of components of the growth hormone-releasing hormone (GHRH) autocrine/paracrine pathway: GHRH and its receptors (GHRH-R), as mammary apocrine carcinomas and epithelium seemed to be uniformly positive for GHRH-R in a pilot study. The apocrine phenotype was determined on the basis of hematoxylin-eosin morphology and a congruent immunohistochemical profile (estrogen receptor negativity, androgen receptor and gross cystic disease fluid protein-15 positivity). Thirty-five formalin-fixed, paraffin-embedded apocrine breast cancers in tissue microarrays and 24 cases using whole-tissue sections were evaluated for GHRH-R and GHRH expression by immunohistochemistry using polyclonal antibodies raised against various domains of GHRH-R and one polyclonal antibody specific for GHRH. GHRH-R positivity was detected in the overwhelming majority (ranging from 90% to 100%) of apocrine breast carcinomas with all but one of the antibodies applied. The expression was usually diffuse with only isolated cases showing positivity in less than 50% of tumor cells. With the PA5-33583 antibody, GHRH-R positivity was seen only in 73% of the cases in at least 50% of the tumor cells. GHRH expression was also present in all but one case tested, with more than 50% of the cells expressing it in 30/34 cases. These results support a high rate of GHRH-R and GHRH expression in apocrine breast carcinomas. Whether these findings can be exploited for the targeted treatment of apocrine breast carcinomas with GHRH antagonists requires further study.

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“…GHRH has been shown to be elevated in some cases in a variety of malignancies including NHL as well as breast, colorectal, renal, and neuroendocrine tumors. 27,35 Evidence supports the mechanism that GHRH is produced by tumor cells and acts in an autocrine fashion to promote tumor growth. In fact, GHRH receptor antagonists have demonstrated efficacy as therapeutic inhibitors of tumor growth.…”

Section: Discussionmentioning

confidence: 90%

“…In fact, GHRH receptor antagonists have demonstrated efficacy as therapeutic inhibitors of tumor growth. 27,35 In the case of our patient, ectopic malignancy producing GHRH was effectively ruled out through thorough whole-body imaging, including PET CT. Therefore, it is reasonable to postulate that the patient's increased GHRH was produced by the lymphoma cells and that the high level acted directly upon nearby somatotrophs to cause hyperplasia and increased growth hormone production, leading to increased IGF-1 level and clinical acromegaly.…”

Section: Discussionmentioning

confidence: 94%

Primary pituitary diffuse large B-cell lymphoma with somatotroph hyperplasia and acromegaly: case report

Ravindra

Raheja

Corn³

et al. 2017

Journal of Neurosurgery

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and comprises approximately 30% of all lymphomas. Patients typically present with a nonpainful mass in the neck, groin, or abdomen associated with constitutional symptoms. In this report, however, the authors describe a rare case of a 61-year-old woman with hyperprolactinemia, hypothyroidism, and acromegaly (elevation of insulin-like growth factor-1 [IGF-1]) with elevated growth hormone-releasing hormone (GHRH) in whom an MRI demonstrated diffuse enlargement of the pituitary gland. Despite medical treatment, the patient had persistent elevation of IGF-1. She underwent a transsphenoidal biopsy, which yielded a diagnosis of DLBCL with an activated B-cell immunophenotype with somatotroph hyperplasia. After stereo-tactic radiation therapy in combination with chemotherapy, she is currently in remission from her lymphoma and has normalized IGF-1 levels without medical therapy, 8 months after her histopathological diagnosis. This is the only reported case of its kind and displays the importance of a broad differential diagnosis, multidisciplinary evaluation, and critical intraoperative decision-making when treating atypical sellar lesions.

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Potentiating effects of GHRH analogs on the response to chemotherapy

Cited by 12 publications

References 56 publications

Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

The expression of GHRH and its receptors in breast carcinomas with apocrine differentiation—further evidence of the presence of a GHRH pathway in these tumors

Primary pituitary diffuse large B-cell lymphoma with somatotroph hyperplasia and acromegaly: case report

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