Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia, Charlottesville, Virginia 22908-0679, USA.
Ann Thorac Surg. 2011 Sep;92(3):1031-7. doi: 10.1016/j.athoracsur.2011.04.081.
With the exception of surgery, the standard platinum-based chemotherapeutic agents are the preferred treatment for non-small cell lung cancer (NSCLC); however little improvement (5-year survival) has been made. Therefore it is highly desirable to develop innovative therapeutic agents for NSCLC treatment.
Highly enantioselective synthetic methods were developed and a broad compound library was established. Cell toxicity, cell sensitivity, cell proliferation, cell invasion, and three-dimensional colony formation assays were used to assess the anticancer potential of these compounds in non-small-cell lung cancer (NSCLC) cell lines.
We found that the S-form of compound PL54 (PL54S, 5-20 μM) exhibited strong anticancer activity in 5 tested NSCLC cell lines. We further synthesized a highly pure R-form enantiomer of PL54 (PL54R) and its racemate (PL54Rac) and characterized their anticancer activities. The results showed that PL54S is more potent than PL54R and PL54Rac against the tested cell lines. Furthermore, less cellular toxicity was observed in the normal human lung fibroblasts. Similarly, PL54S displayed greater anti-colony formation activity compared with PL54R and PL54Rac. The cellular sensitivity assay revealed that PL54S and PL54Rac significantly suppressed cologenic formation compared with PL54R and dimethyl sulfoxide controls (p<0.01). All PL54 compounds (5 to 20 μM) significantly inhibited cell proliferation and invasion of the A549 cell line (p<0.01). A soft agar colony formation assay revealed that PL54S and PL54Rac (10 mM), but not PL54R, significantly inhibited colony formation of tested NSCLC cells (p<0.01).
The stereospecific compounds may prove to be a novel technique for the treatment of NSCLC.
除了手术，标准的铂类化疗药物是治疗非小细胞肺癌（NSCLC）的首选药物；然而，（5 年生存率）几乎没有改善。因此，开发治疗 NSCLC 的创新治疗药物是非常理想的。
开发了高度对映选择性的合成方法，并建立了广泛的化合物库。细胞毒性、细胞敏感性、细胞增殖、细胞侵袭和三维集落形成测定用于评估这些化合物在非小细胞肺癌（NSCLC）细胞系中的抗癌潜力。
我们发现 S 型化合物 PL54（PL54S，5-20 μM）在 5 种测试的 NSCLC 细胞系中表现出强烈的抗癌活性。我们进一步合成了高度纯的 R 型对映异构体 PL54（PL54R）及其外消旋体（PL54Rac），并对其抗癌活性进行了表征。结果表明，PL54S 比 PL54R 和 PL54Rac 对测试的细胞系更有效。此外，在正常的人肺成纤维细胞中观察到的细胞毒性更小。同样，PL54S 显示出比 PL54R 和 PL54Rac 更大的抗集落形成活性。细胞敏感性测定表明，与 PL54R 和二甲亚砜对照相比，PL54S 和 PL54Rac 显著抑制集落形成（p<0.01）。所有 PL54 化合物（5 至 20 μM）均显著抑制 A549 细胞系的细胞增殖和侵袭（p<0.01）。软琼脂集落形成测定显示，PL54S 和 PL54Rac（10 mM），而不是 PL54R，显著抑制测试的 NSCLC 细胞的集落形成（p<0.01）。
立体特异性化合物可能被证明是治疗 NSCLC 的一种新方法。
