Kyakulaga Al Hassan, Aqil Farrukh, Munagala Radha, Gupta Ramesh C
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
Oncotarget. 2020 Apr 21;11(16):1399-1416. doi: 10.18632/oncotarget.27519.
Platinum-taxane combination chemotherapy still represents the standard of care for advanced non-small cell lung cancer (NSCLC) with no targetable driver mutations. However, the efficacy of these drugs has plateaued at 10-14 months primarily due to dose-limiting toxicity, chemoresistance, and metastasis. Here, we explored the effects of withaferin A (WFA) alone and in combination with paclitaxel (PAC) on the growth, proliferation, migration, and invasion of human NSCLC cells. We show that the sensitivity of H1299 and A549 cells to concomitant treatment with PAC and WFA was greater than that of either PAC or WFA alone. Using the combination index and dose-reduction index, we demonstrated that various combinations (1:40, 1:20, 1:10) of PAC to WFA, respectively, were highly synergistic. In addition, PAC+WFA co-treatment synergistically inhibited colony formation, migration, invasion and increased the induction of apoptosis in H1299 and A549 cells. Interestingly, the synergism of PAC and WFA was not schedule-dependent but was enhanced when cells were pretreated with WFA indicating a chemo-sensitizing effect. Importantly, WFA was active against both PAC-sensitive (TS-A549) and PAC-resistant (TR-A549) cells both and . Mechanistically, WFA inhibits the proliferation of NSCLC cells via thiol oxidation. The effects of WFA were inhibited in the presence of N-acetyl cysteine and other thiol donors. Taken together, our results demonstrate the efficacy of WFA alone or alongside PAC on NSCLC cells and provide a strong rationale for further detailed testing in clinically relevant models for the development of PAC+WFA combination as an alternative therapeutic strategy for advanced NSCLC.
铂类-紫杉烷联合化疗仍然是晚期非小细胞肺癌（NSCLC）无可靶向驱动突变情况下的标准治疗方案。然而，这些药物的疗效在10 - 14个月时达到了平台期，主要原因是剂量限制性毒性、化疗耐药性和转移。在此，我们探究了单独使用白藜芦醇A（WFA）以及与紫杉醇（PAC）联合使用对人NSCLC细胞生长、增殖、迁移和侵袭的影响。我们发现，H1299和A549细胞对PAC与WFA联合治疗的敏感性高于单独使用PAC或WFA。通过联合指数和剂量降低指数，我们证明PAC与WFA的各种组合（分别为1:40、1:20、1:10）具有高度协同性。此外，PAC + WFA联合治疗协同抑制了H1299和A549细胞的集落形成、迁移、侵袭，并增加了细胞凋亡诱导。有趣的是，PAC与WFA的协同作用不依赖于给药顺序，但当细胞先用WFA预处理时协同作用增强，表明具有化疗增敏作用。重要的是，WFA对PAC敏感（TS - A549）和PAC耐药（TR - A549）细胞均有活性。从机制上讲，WFA通过硫醇氧化抑制NSCLC细胞的增殖。在存在N - 乙酰半胱氨酸和其他硫醇供体的情况下，WFA的作用受到抑制。综上所述，我们的结果证明了单独使用WFA或与PAC联合使用对NSCLC细胞的疗效，并为在临床相关模型中进一步详细测试以开发PAC + WFA联合方案作为晚期NSCLC的替代治疗策略提供了有力依据。
