Institute of Biomedical Sciences, National Chung Hsing University, No. 145, Xingda Rd., South Dist, Taichung, 40227, Taiwan, Republic of China.
Department of Chemistry, Tunghai University, Taichung, Taiwan.
J Hematol Oncol. 2017 Nov 13;10(1):172. doi: 10.1186/s13045-017-0539-3.
The tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds.
Human non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment. Src and Src-related protein expression in AC-93253 iodide-treated PC9, PC9/gef, and A549 cells were assessed by western blotting. The effects of AC-93253 iodide on cancer cell colony formation, invasion, and migration were assessed in PC9 and PC9/gef cells. The synergistic effects of gefitinib and AC-93253 iodide were evaluated by combination index (CI)-isobologram analysis in gefitinib-resistant cell lines. The efficacy of AC-93253 iodide in vivo was determined using nude mice treated with either the compound or the vehicle.
Among the compounds, AC-93253 iodide exhibited the most potent dose-independent inhibitory effects on the activity of Src as well as on that of the Src-related proteins EGFR, STAT3, and FAK. Furthermore, AC-93253 iodide significantly suppressed cancer cell proliferation, colony formation, invasion, and migration in vitro and tumor growth in vivo. AC-93253 iodide sensitized tumor cells to gefitinib treatment regardless of whether the cells were gefitinib-sensitive (PC9) or resistant (H1975 and PC9/gef), indicating that it may exert synergistic effects when used in combination with established therapeutic agents. Our findings also suggested that the inhibitory effects of AC-93253 iodide on lung cancer progression may be attributable to its ability to modulate multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, MEK, ERK, and EGFR.
Our data suggest that AC-93253 iodide inhibits NSCLC cell growth and motility by regulating multiple Src-related pathways. Our findings may facilitate the development of therapeutic strategies and anti-tumor drugs that may be useful for treating lung cancer in the future.
酪氨酸激酶 Src 参与了许多癌症的进展。此外，抑制 Src 的活性已被证明可以阻止 EGFR 调节的几种信号通路。因此，Src 是药物开发中有价值的靶标分子。本研究的目的是鉴定直接或间接调节 Src 的化合物，以抑制肺癌细胞的生长和迁移，并研究这些化合物作用的分子机制。
用细胞毒性和增殖试验检测不同 EGFR 状态的人非小细胞肺癌（NSCLC）细胞系（PC9、PC9/gef、A549 和 H1975）在 AC-93253 碘化物处理后的反应。通过 Western blot 检测 AC-93253 碘化物处理后的 PC9、PC9/gef 和 A549 细胞中 Src 和 Src 相关蛋白的表达。在 PC9 和 PC9/gef 细胞中评估 AC-93253 碘化物对癌细胞集落形成、侵袭和迁移的影响。通过组合指数（CI）-等对 PC9/gef 细胞中 gefitinib 和 AC-93253 碘化物的协同作用进行了等物线分析。使用裸鼠评估体内 AC-93253 碘化物的疗效，裸鼠接受化合物或载体处理。
在这些化合物中，AC-93253 碘化物对 Src 及其 Src 相关蛋白 EGFR、STAT3 和 FAK 的活性表现出最有效的、非剂量依赖性的抑制作用。此外，AC-93253 碘化物显著抑制了癌细胞的体外增殖、集落形成、侵袭和迁移以及体内肿瘤生长。AC-93253 碘化物使肿瘤细胞对 gefitinib 治疗敏感，无论细胞是否对 gefitinib 敏感（PC9）或耐药（H1975 和 PC9/gef），这表明它与已建立的治疗剂联合使用可能会产生协同作用。我们的研究结果还表明，AC-93253 碘化物对肺癌进展的抑制作用可能归因于其调节多种蛋白的能力，包括 Src、PI3K、JNK、Paxillin、p130cas、MEK、ERK 和 EGFR。
我们的数据表明，AC-93253 碘化物通过调节多种 Src 相关途径抑制 NSCLC 细胞的生长和迁移。我们的研究结果可能有助于开发治疗策略和抗肿瘤药物，这可能对未来治疗肺癌有用。
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