Discovery of LHRH and development of LHRH analogs for prostate cancer treatment

Schally, Andrew V.; Block, Norman L.; Rick, Ferenc G.

doi:10.1002/pros.23360

Cited by 41 publications

(36 citation statements)

References 160 publications

(281 reference statements)

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“…This suggests that the down-regulation of GHRH-Rs leads to an inhibition of tumor growth. This situation appears to be similar and comparable to the well-known phenomenon of the down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LHRH) by LHRH agonists (44)(45)(46). It is well established that an acute administration of superactive agonists of LHRH induces a marked release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).…”

Section: Discussionsupporting

confidence: 68%

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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: Discussionsupporting

confidence: 68%

“…However, chronic administration of LHRH or its agonists leads to a suppression of circulating levels of FSH, LH, and sex steroids. This effect is produced by the desensitization of gonadotroph cells and the downregulation of pituitary receptors for LHRH and is utilized for the inhibition of sex hormone-dependent cancers (44)(45)(46).…”

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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“…Currently, two types of GnRH-R are known to exist in primates, with only a functional type I GnRH-R existing in human tissues (4). Studies have demonstrated that GnRH-R is overexpressed in many human tumors (e.g., breast, ovarian, endometrial, and prostate cancers), whereas it is not expressed or expressed at very low levels in adjacent normal tissues (5)(6)(7). Accumulating evidence has demonstrated that more than 80% of ovarian and endometrial cancers, as well as more than 50% of breast cancers, have high levels of GnRH-R expression (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

Pradeep

Villar‐Prados

et al. 2019

Molecular Cancer Therapeutics

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EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. EP-100 decreased the viability of ovarian cancer cells and reduced tumor growth in orthotopic mouse models. Of five standard drugs tested (cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib), we found that the combination of EP-100 and olaparib was synergistic in ovarian cancer cell lines. Further experiments revealed that combined treatment of EP-100 and olaparib significantly increased the number of nuclear foci of phosphorylated histone H2AX. In addition, the extent of DNA damage was significantly increased after treatment with EP-100 and olaparib in comet assay. We performed reverse-phase protein array analyses and identified that the PI3K/AKT pathway was inhibited by EP-100, which we validated with in vitro experiments. In vivo experiment using the HeyA8 mouse model demonstrated that mice treated with EP-100 and olaparib had lower tumor weights (0.06 AE 0.13 g) than those treated with a vehicle (1.19 AE 1.09 g), EP-100 alone (0.62 AE 0.78 g), or olaparib alone (0.50 AE 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer.

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“…Finally, we note that an luteinizing‐hormone releasing hormone (LHRH) antagonist (Cetrorelix), which brought down serum testosterone to castrate levels in a rat model of BPH, reduced prostate size and blunted the expression of pro‐inflammatory cytokines and growth factors . Accordingly, the suitability of LHRH antagonism in BPH therapy is currently being explored . We speculate that the androgen/androgen receptor (AR)‐regulated signaling network may be impacted by the SASP secretome, and genetic or pharmacologic targeting of downstream effectors of the AR pathway may further inform new avenues for controlling BPH pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of prostate cells by the senescence phenotype of epithelial and stromal cells: Implication for benign prostate hyperplasia

2019

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Hyperproliferation of prostate transition‐zone epithelial and stromal cells leads to benign prostate hyperplasia (BPH), a prevalent pathology in elderly men. Senescent cells in BPH tissue induce a senescence‐associated secretory phenotype (SASP) which, by generating inflamed microenvironment and reactive stroma, promotes leukocyte infiltration, cellular hyperproliferation, and nodular prostate growth. We examined human prostate epithelial (BPH‐1, PNT‐1α) and stromal (HPS‐19I) cells for SASP induction by ionizing radiation and assessed SASP's impacts on cell proliferation and on signal transducers that promote cellular growth, proliferation, and survival. Radiation‐induced DNA damage led to cellular senescence, evident from elevated expression of senescence‐associated β‐galactosidase and the cell‐cycle inhibitor p16/INK4a. Clinical BPH tissue showed p16 accumulation. SASP induced mRNA expression for inflammatory cytokines (IL‐1α, IL‐6, IL‐8, TNF‐α); chemokines (GM‐CSF, CXCL12); metalloproteases (MMP‐1, MMP‐3, MMP‐10); growth factor binding IGFBP‐3. Media from irradiated epithelial or stromal cells enhanced BPH‐1 proliferation. ERK1/2 and AKT, which enhance cell growth/survival and STAT5, which facilitates cell cycle progression and leukocyte recruitment to epithelial microenvironment, were activated by SASP components. The radiation‐induced cellular senescence model can be a platform for identification of individual SASP components and pathways that drive BPH etiology/progression in vivo and targeting them may form the basis for novel BPH therapy.

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Discovery of LHRH and development of LHRH analogs for prostate cancer treatment

Cited by 41 publications

References 160 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

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

Stimulation of prostate cells by the senescence phenotype of epithelial and stromal cells: Implication for benign prostate hyperplasia

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