Growth Hormone-Releasing Hormone Antagonists Increase Radiosensitivity in Non-Small Cell Lung Cancer Cells

TL;DR

This study shows that GHRH antagonists can make non-small cell lung cancer cells more sensitive to radiation therapy, improving treatment effectiveness.

Contribution

The study demonstrates that GHRH antagonists enhance radiosensitivity in NSCLC cells through multiple molecular mechanisms.

Findings

GHRH antagonists alone and in combination with radiation reduced cell viability and proliferation in NSCLC cells.

MIA-690 decreased GHRH receptor and IGF1 expression while upregulating proapoptotic markers and cell cycle inhibitors.

GHRH antagonists reduced radioresistance and epithelial-mesenchymal transition markers in NSCLC cells.

Abstract

Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell lines were exposed to ionizing radiation (IR) and GHRH antagonists MIA-602 and MIA-690, either individually or in combination. Cell viability and proliferation were evaluated by MTT, BrdU, flow cytofluorimetry, and clonogenic assays; gene and protein expression, signaling pathways, and apoptosis were analyzed by real-time PCR, Western blot, annexin staining, and caspase-3 assay. GHRH antagonists showed antitumor effects alone and potentiated IR-induced inhibition of cell viability and proliferation. The combination of MIA-690 and IR decreased the expression of GHRH receptor, its oncogenic splice variant 1, and IGF1 mRNA levels. Additionally, cell cycle inhibitors and proapoptotic markers were upregulated, whereas cyclins, oncogenic MYC, and the antiapoptotic protein Bcl-2 were downregulated. Radioresistance was prevented by MIA-690, which also blunted epithelial–mesenchymal transition by enhancing E-cadherin and reducing mesenchymal, oxidative, and proangiogenic effectors. Finally, both MIA-602 and MIA-690 enhanced radiosensitivity in primary human NSCLC cells. These findings highlight the potential of GHRH antagonists as radiosensitizers in NSCLC treatment.

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