Simple SummaryPreviously, it has been shown that the use of growth hormone–releasing hormone (GHRH) antagonistic peptide analogs significantly suppresses the proliferation of various human cancer cell lines. However, the potential of the GHRH antagonist MIA-602 in addressing the resistance of acute promyelocytic leukemia (APL), as well as its ability to produce synergistic effects in acute myeloid leukemia (AML), have not yet been studied. Our findings indicate that the APL double-resistant cell line (NB4-RAA) and the K-562 AML cell line possess the GHRH receptor (GHRH-R) and are thus susceptible to treatment. We further described neural cell adhesion molecule 1 (NCAM1 classified as CD56) and its association with resistance to standard APL treatment in our in vitro model.AbstractGHRH is a hypothalamic peptide shown to stimulate the proliferation of malignant cells in humans. We have previously shown that the use of GHRH antagonist MIA-602 successfully suppressed the growth of many human cancer cell lines, spanning more than 20 types of cancers. In this study, we demonstrate the presence of GHRH-R in the NB4, NB4-RAA, and K-562 model cell lines. Furthermore, we demonstrate the inhibited proliferation of all three cell lines in vitro after incubation with MIA-602. The treatment of xenografts of human APL cell lines with MIA-602 led to a significant reduction in tumor growth. Additionally, combination therapy with both doxorubicin (DOX) and MIA-602 showed a marked synergistic effect in reducing the proliferation of the K-562 AML cell line. These findings suggest that MIA-602 could be utilized to address resistance to all-transretinoic acid (ATRA) and arsenic trioxide (ATO) therapies, as well as in augmenting anthracycline-based regimens.