Synergistic combinations of paclitaxel and withaferin A against human non-small cell lung cancer cells

Abstract

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 dosereduction 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 in vitro and in vivo. 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.

Paclitaxel-Based Chemotherapy Targeting Cancer Stem Cells from Mono- to Combination Therapy

“…Thus, the sensitivity of H1299 and A549 cells to the treatment was shown to be greater in the combination of PTX with WFA than in the single use of either PTX or WFA alone. These findings validate the use of WFA alone or with PTX in NSCLC cells and justify the further testing of clinically relevant models with the combination of PTX and WFA of advanced NSCLC as an alternative to current therapeutic strategies [ 172 ].…”

Targeted Oral Delivery of Paclitaxel Using Colostrum-Derived Exosomes

“…The effect of PAC and its exosomal formulation on cell viability was measured using the MTT assay. Briefly, A549 and A549TR cells were plated in 96-well plates at an initial density of 3 × 10 3 cells per well and treated with Exo, PAC or ExoPAC and incubated for 72 h. The cell survival was determined by MTT assay, as described [26]. Briefly, A549-LUC cells (3 × 10 3 cells/well) were plated in 96-well white plates.…”

“…Taxol-sensitive (A549) and taxol-resistant (A549TR) cells were seeded into 6-well tissue culture plates at a density of 500 cells/well, as described [26]. The cells were treated with PAC or ExoPAC at different concentrations for 24 h. The drug-containing medium was discarded and replaced with a fresh drug-free medium.…”

Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

“…An alternative strategy to minimize potential adverse effects and lower the doses of WA could be to investigate the synergistic effects of WA with other anti-inflammatory drugs. This approach is already being broadly investigated in several cancer models [ 141 , 142 ]. In a clinical trial combining the use of five Ayurvedic herbal formulations ( Zingiber officinale , Tinospora cordifolia , Emblica officinalis , Tribulus terrestris and Withania somnifera ) in the treatment of osteoarthritis seemed to significantly relieve pain in the majority of patients [ 143 ].…”