In this new study, researchers examined the impact of MIA-602 as monotherapy and in combination with Doxorubicin on three Doxorubicin-resistant acute myeloid leukemia cell lines.
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Upon diagnosing acute myeloid leukemia (AML), the initial step involves assessing a patient’s eligibility for intensive chemotherapy. The standard treatment protocol for newly diagnosed AML encompasses intensive chemotherapy to achieve complete remission, followed by post-remission therapy, which may include additional chemotherapy and/or stem cell transplantation. Complete response rates to this approach range from 60% to 85% in adults aged 60 or younger.
While this approach has proven effective, the risk of relapse within three years of diagnosis remains a significant concern. Numerous factors contribute to the likelihood of relapse, including short duration of remission, genetic derangements, prior allogeneic transplantation, advanced age, and concomitant comorbidities. These negative prognostic factors underscore the need for continuous exploration of novel therapeutic agents, as relapse remains a formidable barrier to treatment success.
In a new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally (awarded the Nobel Prize in Physiology or Medicine in 1977), and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami, investigated newly emerging therapies targeting drug resistance in AML. On April 8, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.”
Drug Resistance: A Persistent Obstacle
Drug resistance poses a substantial challenge in the treatment of AML, often hindering successful outcomes. This resistance can manifest in two distinct forms:
- Primary Drug Resistance: Inherent resistance to specific therapeutic agents, present from the outset of treatment.
- Acquired Drug Resistance: Resistance developed over the course of treatment, potentially due to various underlying mechanisms.
These resistance pathways involve intricate interplay between drug resistance-related proteins, enzymes, genes, microRNAs, and aberrant signaling pathways, highlighting the complexity of this phenomenon.
Exploring the Potential of GHRH Antagonists in AML Treatment
Growth hormone-releasing hormone (GHRH) is a neuropeptide hormone primarily released by the hypothalamus, canonically known for its role in inducing the release of growth hormone from the pituitary gland. However, GHRH’s influence extends beyond this endocrine axis, acting as a growth factor in various cancer types and normal tissues through an autocrine/paracrine mechanism.
Previous studies have demonstrated the expression of GHRH receptors (GHRH-R) in human AML cell lines, including K-562, THP-1, and KG-1A. Notably, the GHRH antagonist MIA-602 has exhibited the ability to inhibit the proliferation of these leukemic cells both in vitro and in preclinical mouse models.
MIA-602, a synthetic GHRH antagonist, has garnered significant attention for its potential in circumventing drug resistance and mitigating the adverse effects associated with conventional chemotherapy. Numerous studies have documented the anti-oncogenic mechanisms of GHRH antagonists, which encompass:
-Downregulation of NF-κB and beta-catenin
-Upregulation of caveolin-1 and E-cadherin
-Activation of pro-apoptotic pathways
-Modulation of inflammatory cytokines
-Inhibition of the Akt signaling pathway
These diverse mechanisms underscore the multifaceted approach through which MIA-602 exerts its anti-cancer effects, targeting various aspects of oncogenesis, including cellular proliferation, survival, and motility. Importantly, GHRH antagonists have been implicated in the in vitro inhibition of a wide range of cancer cell lines, spanning from acute promyelocytic leukemia (APL) and AML to estrogen-independent breast cancer, clear cell ovarian cancer, glioblastoma, gastric cancer, prostate cancer, and endometrial adenocarcinoma.
Investigating the Impact of MIA-602 on Doxorubicin-Resistant AML Cell Lines
In Vitro Evaluation: Unveiling Promising Results
In the current study, Gaumond et al. evaluated the impact of MIA-602 as a monotherapy and in combination with the chemotherapeutic agent Doxorubicin on three Doxorubicin-resistant AML cell lines: KG-1A, U-937, and K-562. The in vitro results revealed a remarkable reduction in cell viability across all treated wild-type cells, underscoring the efficacy of MIA-602.
Notably, the Doxorubicin-resistant clones exhibited a comparable susceptibility to MIA-602 as their wild-type counterparts. This finding suggests that MIA-602’s mechanism of action is distinct from that of Doxorubicin, enabling it to circumvent the resistance pathways that render Doxorubicin ineffective.
When treated with MIA-602 alone, the following decreases in cell viability were observed:
-KG-1A: 53.5% (wild-type) and 54.5% (Doxorubicin-resistant)
-U-937: 49% (wild-type) and 51.25% (Doxorubicin-resistant)
-K-562: 79.25% (both wild-type and Doxorubicin-resistant)
These results highlight the potent anti-proliferative effects of MIA-602 on AML cell lines, irrespective of their Doxorubicin resistance status. Furthermore, the combination treatment of Doxorubicin and MIA-602 yielded even more remarkable outcomes:
-KG-1A: 80.25% decrease in wild-type cell viability and 57.5% reduction in Doxorubicin-resistant cells
-U-937: 92.5% decrease in wild-type cells and 52.75% reduction in Doxorubicin-resistant cells
-K-562: 88.75% reduction in wild-type cell viability and 78.25% decrease in Doxorubicin-resistant cells
These findings suggest a potential synergistic effect between MIA-602 and Doxorubicin, highlighting the therapeutic potential of this combination approach in overcoming drug resistance.
In Vivo Validation: Corroborating the Therapeutic Efficacy
To further substantiate the in vitro observations, an in vivo experiment was conducted using nude mice xenografted with Doxorubicin-resistant K-562 cells. The mice were randomly divided into two groups: one receiving a control diluent and the other treated with MIA-602 at a dose of 10 μg twice daily for 28 days.
After the treatment period, the control group exhibited a tumor volume of 1114 mm³, while the MIA-602 monotherapy group demonstrated a significantly reduced tumor volume of 629 mm³ – a remarkable decrease of 485 mm³. This finding further reinforces the therapeutic potential of MIA-602 in combating Doxorubicin-resistant AML.
Exploring the Mechanisms of Action and Future Directions
While the anti-oncogenic mechanisms of GHRH antagonists have been extensively studied in various cancer types, further investigation is warranted to elucidate the specific transcriptional effects of GHRH antagonism in Doxorubicin-resistant AML cell lines. Understanding these molecular pathways could pave the way for more targeted and effective therapeutic strategies.
Another area of interest lies in exploring the potential influence of genetic AML subtypes on the response to GHRH antagonist therapy. By examining the expression levels of GHRH receptors across different AML subtypes, researchers can gain insights into the therapeutic potential of MIA-602 and its potential for personalized treatment approaches.
The observed synergistic effects of MIA-602 and Doxorubicin in combating Doxorubicin-resistant AML cell lines warrant further exploration of combination therapies. By strategically combining MIA-602 with other chemotherapeutic agents or targeted therapies, researchers may uncover novel treatment regimens with enhanced efficacy and reduced adverse effects.
Ultimately, the successful translation of these preclinical findings to clinical settings will be crucial in realizing the full potential of MIA-602 as a therapeutic option for Doxorubicin-resistant AML. Well-designed clinical trials will be essential to evaluate the safety, efficacy, and optimal dosing regimens of MIA-602, both as a monotherapy and in combination with other treatments.
Conclusion: Paving the Way for Improved Outcomes
The discovery of MIA-602’s ability to overcome Doxorubicin resistance in acute myeloid leukemia represents a significant step forward in the quest for more effective and targeted therapies. By leveraging the unique mechanisms of action of GHRH antagonists, researchers have unveiled a promising therapeutic approach that circumvents the limitations of conventional chemotherapy.
While further research is necessary to fully elucidate the underlying molecular pathways and optimize treatment strategies, the findings presented in this study offer hope for improved outcomes in patients with Doxorubicin-resistant AML. By continuing to explore the potential of novel agents like MIA-602, the scientific community moves closer to achieving the ultimate goal of personalized, effective, and well-tolerated treatments for this challenging malignancy.
Click here to read the full research paper in Oncotarget.
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