Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists

Abstract

The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGFβ. Proteomic and geneexpression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and antiinvasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells.peptide analogs | targeted therapy

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

“…The mechanisms of inhibition of tumor growth in vivo by the treatment with GHRH agonists are still unclear. A potentiating effect of GHRH and its agonists on the response to chemotherapy has been previously reported (42). Exposure of glioblastoma U-87 MG cells to the GHRH agonist JI34 in vitro augmented the inhibitory effect of doxorubicin on cell proliferation.…”

Tumor-Associated and Disease-Associated Autoantibody Repertoires in Healthy Colostrum and Maternal and Newborn Cord Sera

“…Note that most of the highly reactive, prevalent autoantibodies shown in Table I have some association with cancer-related selfAgs, including BIRC2 (41), CA125 (43), MUC1 (54), stem cell factor (60), S-100 (61), myosin (56), GHRH (26,27), glucagon (29), HGH (31), leptin (33), F3 coagulation factor III (36), EEF1A1 (45), fibronectin (48,49), neurotrophin-3 (58), BCMO1 (63), citrate synthase (66), GST (68), PTGDS (70), laminin (83), and MIF (85). Indeed, we have found that dynamic changes in autoantibody repertoires mark the natural history in mice of variants of a syngeneic, transplantable tumor (112).…”

Potentiating effects of GHRH analogs on the response to chemotherapy

“…50 Similarly in vivo, treatment with a combination of doxorubicin and a GHRH agonist suppresses the growth of U87 MG glioblastoma tumors xenografted into nude mice more than doxorubicin alone. 50 The recognition of potentiation of anticancer activity by GHRH agonists is being investigated.…”

“…50 Similarly in vivo, treatment with a combination of doxorubicin and a GHRH agonist suppresses the growth of U87 MG glioblastoma tumors xenografted into nude mice more than doxorubicin alone. 50 The recognition of potentiation of anticancer activity by GHRH agonists is being investigated. Among many possibilities, this effect may be attributed to the ability of GHRH agonists to produce changes in the cell maturation state, leading to an alteration of the pluripotency of CSC.…”

“…While GHRH antagonists potentially inhibit the formation of CSCs through the dedifferentiation of tumor cells through EMT, it is also possible that GHRH agonists suppress the CSC population by inducing their differentiation by the mechanism of EMT. 50 A downregulation of receptors for GHRH, similar to that which occurs with receptors for LHRH and which is the basis of therapy of prostate cancer with LHRH agonist, [51][52][53][54] could be theoretically involved in inhibition of tumor growth by the agonists or the antagonists of GHRH; this phenomenon is being carefully investigated.…”