The Application of GHRH Antagonist as a Treatment for Resistant APL

Abstract

GHRH 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-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapies, as well as in augmenting anthracycline-based regimens.

Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia

“…Our preliminary study tested varying concentrations of Doxorubicin ranging from 0.005, 0.01 and 0.05 μg/ml, in which we determined the ED-50 to be 0.01 μg [ 10 ]. We then cultured both wild-type (W-T) and Doxorubicin-resistant (D-R) clones with MIA-602 at concentrations ranging from 0.05 μmol/L to 5 μmol/L, for 24 and 48 hours.…”

“…We then cultured both wild-type (W-T) and Doxorubicin-resistant (D-R) clones with MIA-602 at concentrations ranging from 0.05 μmol/L to 5 μmol/L, for 24 and 48 hours. The optimal concentration of MIA-602 was determined to be 5 μmol/L [ 9 , 10 ]. We then demonstrated the presence of GHRH receptor (GHRH-R) in both W-T and D-R cell lines by western blot [ 10 ].…”

“…The optimal concentration of MIA-602 was determined to be 5 μmol/L [ 9 , 10 ]. We then demonstrated the presence of GHRH receptor (GHRH-R) in both W-T and D-R cell lines by western blot [ 10 ]. Since we have previously shown that both the wild-type and the Doxorubicin clones had positive expression of GHRH-R, we hypothesize that MIA-602 could be a beneficial targeted therapy for AML.…”

“…We have previously demonstrated the expression of GHRH-R in human AML cell lines K-562, THP-1, and KG-1A [ 9 ]. We have also demonstrated the ability of MIA-602, a GHRH antagonist, to inhibit the proliferation of these leukemic cells in vitro as well as in preclinical mouse models [ 9 , 10 ]. Furthermore, we have investigated MIA-602’s utility in treating all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) resistant cells [ 10 ].…”

“…We have also demonstrated the ability of MIA-602, a GHRH antagonist, to inhibit the proliferation of these leukemic cells in vitro as well as in preclinical mouse models [ 9 , 10 ]. Furthermore, we have investigated MIA-602’s utility in treating all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) resistant cells [ 10 ]. Given the role of GHRH in multiple cancer types, it is possible that GHRH antagonists may offer an alternative treatment approach for AML as well as drug-resistant AML, which may circumvent the side effects associated with standard chemotherapy.…”