Antagonist of growth hormone-releasing hormone MIA-690 attenuates the progression and inhibits growth of colorectal cancer in mice.
Antagonist of growth hormone-releasing hormone MIA-690 attenuates the progression and inhibits growth of colorectal cancer in mice.
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DOI：
10.1016/j.biopha.2021.112554
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发表时间：
2021-12
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通讯作者：
L. Recinella;A. Chiavaroli;S. Veschi;V. Di Valerio;R. Lattanzio;G. Orlando;C. Ferrante;Iacopo Gesmundo;R. Granata;R. Cai;W. Sha;A. Schally;L. Brunetti;S. Leone
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作者：
L. Recinella;A. Chiavaroli;S. Veschi;V. Di Valerio;R. Lattanzio;G. Orlando;C. Ferrante;Iacopo Gesmundo;R. Granata;R. Cai;W. Sha;A. Schally;L. Brunetti;S. Leone
结直肠癌(CRC)是一种侵袭性肿瘤，其新的治疗方案对治愈率和长期生存率都是负面的。生长激素释放激素(GHRH)拮抗剂在各种实验性肿瘤中的抗癌作用已有报道，但其在结直肠癌中的活性尚不清楚。在目前的研究中，我们证明了迈阿密类GHRH拮抗剂MIA-690的慢性治疗可以提高小鼠实验性结肠炎相关癌症的存活率，并逐渐减缓肿瘤的进展，同时减少结肠组织的炎症。特别是，与赋形剂治疗组相比，MIA-690通过提高存活率，改善了疾病活动指数评分，并减少了体重减轻和死亡率。MIA-690还可降低多种炎症和氧化标志物，如5-羟色胺、前列腺素E2和8-iso-PGF2的α水平，以及COX-2、诱导型一氧化氮合酶、肿瘤坏死因子-α、IL-6和核因子-kB的基因表达。MIA-690还可抑制c-Myc、P-AKT和Bcl2蛋白的表达，上调P53蛋白的表达。综上所述，我们发现MIA-690通过减少炎症和氧化标记物以及调节凋亡和致癌途径来抑制结直肠癌的进展和生长。需要进一步的调查才能将这些发现转化为诊所。
Colorectal cancer (CRC) is an aggressive tumor in which new treatment options deliver negative results on cure rates and long-term survival. The anticancer effects of growth hormone-releasing hormone (GHRH) antagonists have been reported in various experimental tumors, but their activity in CRC is unknown. In the present study, we demonstrated that chronic treatment with GHRH antagonist of MIAMI class, MIA-690, promoted survival and gradually blunted tumor progression in experimentally induced colitis-associated cancer in mice, paralleled by reduced inflammation in colon tissue. In particular, MIA-690 improved disease activity index score, and reduced loss of weight and mortality, by improving the survival rates, compared with vehicle-treated group. MIA-690 was also found to reduce various inflammatory and oxidative markers, such as serotonin, prostaglandin (PG)E2and 8-iso-PGF2αlevels, as well as COX-2, iNOS, TNF-α, IL-6 and NF-kB gene expression. Moreover, MIA-690 inhibited the protein expression of c-Myc, P-AKT and Bcl-2 and upregulated p53 protein expression. In conclusion, we showed that MIA-690 suppresses CRC progression and growth by reducing inflammatory and oxidative markers and modulating apoptotic and oncogenic pathways. Further investigations are required for translating these findings into the clinics.