Gunasekaran Pethaiah, Han Ho Jin, Choi Jung Hoon, Ryu Eun Kyoung, Park Nam Yeong, Bang Geul, La Yeo Kyung, Park Sunghyun, Hwang Kyubin, Kim Hak Nam, Kim Mi-Hyun, Jeon Young Ho, Soung Nak-Kyun, Bang Jeong Kyu
Division of Magnetic Resonance, Korea Basic Science Institute (KBSI), Ochang, Cheongju 28119, Korea.
Dandicure Inc., Ochang, Cheongju 28119, Korea.
Pharmaceutics. 2021 Dec 3;13(12):2071. doi: 10.3390/pharmaceutics13122071.
Cancer has been identified as a leading cause of death worldwide, and the increasing number of cancer cases threatens to shorten the average life expectancy of people. Recently, we reported a 3-azido-3-deoxythymidine (AZT)-based amphipathic small molecule, ADG-2e that revealed a notable potency against tumor metastasis. To evaluate the anticancer potential of ADG-2e, we assessed its anticancer potency in vitro and in vivo. Anticancer screening of ADG-2e against cervical cancer cells, HeLa CCL2, and BT549 mammary gland ductal carcinoma showed significant inhibition of cancer cell proliferation. Furthermore, mechanistic investigations revealed that cancer cell death presumably proceeded through an oncosis mechanistic pathway because ADG-2e treated cells showed severe damage on the plasma membrane, a loss of membrane integrity, and leakage of -tubulin and -actin. Finally, evaluation of the antitumorigenic potential of ADG-2e in mouse xenograft models revealed that this compound potentially inhibits cancer cell proliferation. Collectively, these findings suggest that ADG-2e can evolve as an anticancer agent, which may represent a model for nucleoside-based small molecule anticancer drug discovery.
癌症已被确认为全球主要死因，癌症病例数量的不断增加可能会缩短人们的平均预期寿命。最近，我们报道了一种基于3-叠氮基-3-脱氧胸苷（AZT）的两亲性小分子ADG-2e，它对肿瘤转移显示出显著的效力。为了评估ADG-2e的抗癌潜力，我们在体外和体内评估了它的抗癌效力。对ADG-2e针对宫颈癌细胞HeLa CCL2和BT549乳腺导管癌进行的抗癌筛选显示，癌细胞增殖受到显著抑制。此外，机制研究表明，癌细胞死亡可能是通过胀亡机制途径进行的，因为经ADG-2e处理的细胞在质膜上显示出严重损伤、膜完整性丧失以及微管蛋白和肌动蛋白泄漏。最后，在小鼠异种移植模型中对ADG-2e的抗肿瘤潜力评估表明，该化合物可能抑制癌细胞增殖。总体而言，这些发现表明ADG-2e可以发展成为一种抗癌剂，这可能代表了基于核苷的小分子抗癌药物发现的一个模型。
