Lurasidone Sensitizes Cancer Cells to Osimertinib by Inducing Autophagy and Reduction of Survivin
Lurasidone Sensitizes Cancer Cells to Osimertinib by Inducing Autophagy and Reduction of Survivin
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DOI：
10.21873/anticanres.15237
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发表时间：
2021-09
影响因子：
2
通讯作者：
Shuhei Suzuki;Masahiro Yamamoto;Tomomi Sanomachi;Keita Togashi;Shizuka Seino;Asuka Sugai;T. Yoshioka;M. Okada;C. Kitanaka
中科院分区：
文献类型：
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作者：
Shuhei Suzuki;Masahiro Yamamoto;Tomomi Sanomachi;Keita Togashi;Shizuka Seino;Asuka Sugai;T. Yoshioka;M. Okada;C. Kitanaka
背景/目的：表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKI）因其不良反应小、抗肿瘤作用突出而成为肿瘤治疗的关键药物。然而，迄今为止，用于克服EGFR-TKI抗性的药物尚未在临床上使用。因此，为了克服耐药性，我们重点研究了鲁拉西酮（一种新型抗精神病药物），因为从药物重新定位的角度来看，其不良反应轻微。材料与方法：我们探索了鲁拉西酮单独给药或与EGFR-TKI联合给药对奥西替尼耐药癌细胞生长、抗凋亡标志物表达（如生存素）和自噬水平（通过LC-3B表达）的影响。结果如下：在正常细胞的无毒浓度范围内，鲁拉西酮和奥希替尼联合治疗在体外和体内对奥希替尼耐药癌细胞显示出生长抑制作用。此外，鲁拉西酮降低了生存素表达并轻度诱导自噬。结论：在药物再利用过程中，鲁拉西酮可能会增加奥希替尼耐药癌细胞对奥希替尼的敏感性。
Background/Aim: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. Materials and Methods: We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. Results: Within a non-toxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. Conclusion: Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.