National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, Shaanxi, China.
National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, Shaanxi, China.
Biochem Pharmacol. 2018 Apr;150:72-85. doi: 10.1016/j.bcp.2018.01.031. Epub 2018 Jan 31.
Non-small cell lung cancer (NSCLC) is the most common malignancy worldwide. A significant fraction of NSCLC carries activating mutations in epidermal growth factor receptor (EGFR) or RAS oncogene. Dihydroartemisinin (DHA) is a semisynthetic derivative of the herbal antimalarial drug artemisinin that has been recently reported to exhibit anti-cancer activity. To develop new therapeutic strategies for NSCLC, we investigated the interactions between DHA and ABT-263 in NSCLC cells harboring EGFR or RAS mutation. Our data indicated that DHA synergized with ABT-263 to trigger Bax-dependent apoptosis in NSCLC cells in culture. DHA treatment antagonized ABT-263-induced Mcl-1 upregulation and sensitized NSCLC cells to ABT-263-triggered apoptosis. Additionally, DHA treatment caused downregulation of Survivin and upregulation of Bim, which also contribute to cotreatment-induced cytotoxicity. Moreover, DHA effectively suppressed STAT3 phosphorylation, and STAT3 inactivation resulted in the downregulation of Mcl-1 and Survivin, functioning to enhance ABT-263-induced cytotoxicity. Finally, cotreatment of DHA and ABT-263 significantly inhibited xenograft growth in nude mice. Together, DHA effectively inhibits STAT3 activity and modulates expression of Mcl-1, Survivin and Bim, thereby synergizing with ABT-263 to trigger apoptosis in NSCLC cells harboring EGFR or RAS mutation. Our data provide a novel therapeutic strategy for EGFR or RAS mutant NSCLC treatment.
非小细胞肺癌（NSCLC）是全球最常见的恶性肿瘤。相当一部分 NSCLC 携带表皮生长因子受体（EGFR）或 RAS 癌基因的激活突变。二氢青蒿素（DHA）是青蒿素这种草药抗疟药物的半合成衍生物，最近有报道称其具有抗癌活性。为了为 NSCLC 开发新的治疗策略，我们研究了 DHA 和 ABT-263 在携带 EGFR 或 RAS 突变的 NSCLC 细胞中的相互作用。我们的数据表明，DHA 与 ABT-263 协同作用，在培养的 NSCLC 细胞中触发 Bax 依赖性细胞凋亡。DHA 处理拮抗 ABT-263 诱导的 Mcl-1 上调，并使 NSCLC 细胞对 ABT-263 触发的凋亡敏感。此外，DHA 处理导致 Survivin 下调和 Bim 上调，这也有助于协同治疗诱导的细胞毒性。此外，DHA 有效抑制 STAT3 磷酸化，STAT3 失活导致 Mcl-1 和 Survivin 下调，增强 ABT-263 诱导的细胞毒性。最后，DHA 和 ABT-263 的联合治疗显著抑制了裸鼠异种移植物的生长。总之，DHA 有效抑制 STAT3 活性并调节 Mcl-1、Survivin 和 Bim 的表达，从而与 ABT-263 协同作用，在携带 EGFR 或 RAS 突变的 NSCLC 细胞中触发细胞凋亡。我们的数据为 EGFR 或 RAS 突变型 NSCLC 的治疗提供了一种新的治疗策略。
