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Combinations of paclitaxel and withaferin A against human non-small cell lung cancer


FOR IMMEDIATE RELEASE
2020-04-22

Oncotarget Volume 11 Issue 16 showed 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.

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.

Taken together, the 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.

Dr. Ramesh C. Gupta from The Department of Pharmacology and Toxicology and The James Graham Brown Cancer Center at The University of Louisville as well as Dr. Farrukh Aqil from The Department of Medicine and The James Graham Brown Cancer Center at The University of Louisville said, "Lung cancer remains the leading cause of cancer-related deaths among both men and women in the U. S and worldwide."

"Lung cancer remains the leading cause of cancer-related deaths among both men and women in the U. S and worldwide."

- Dr. Ramesh C. Gupta, The Department of Pharmacology and Toxicology and The James Graham Brown Cancer Center at The University of Louisville and Dr. Farrukh Aqil from The Department of Medicine and The James Graham Brown Cancer Center at The University of Louisville

The therapeutic options for NSCLC following diagnosis are dependent upon the clinical stage at diagnosis with surgical resection being the standard of care for early-stage NSCLC.

This is true primarily because < 30% of all NSCLC patients show targetable mutations, while anti-PD-1 drugs are effective only in patients with tumors expressing PDL-1 on >50% of tumor cells.

Therefore, despite these recent therapeutic advancements, NSCLC remains largely incurable, and the overall clinical benefit of current therapies in NSCLC is still marginal and temporary.

While PAC and cis-Pt display high antitumor potency and efficacy against all subtypes NSCLC, this chemotherapy suffers from a lack of selectivity, dose-limiting toxicity, drug resistance, and metastasis which have plateaued the clinical efficacy at about 10-14 months.

Figure 1: WFA inhibits NSCLC cell proliferation via thiol dependent induction of apoptosis. (A) Chemical structure of WFA. Cells were incubated with WFA for 3, 6, 12, 48 and 72 h and cell viability measured at 72 h. WFA dose-dependently inhibited the proliferation of H1299 (B) and A549 cells (C). (D) AnnexinV/PI assay depicting induction of apoptosis at 2 μM concentration of WFA compared to DMSO control. (E) Western blot analysis indicated increased expression of p21, phospho-H3, and cleavage of caspase-3 at different concentration of WFA (0, 0.2, 1, and 4 μM). ROS determination by fluorescent microscopy using the H2DCFDA assay (F) and Mitosox Red (H) indicated the induction of reactive oxygen species (ROS) production in H1299 and A549 cells. The induction of ROS by WFA was significantly inhibited in the presence of the thiol donor, N-acetyl cysteine (NAC). H2O2 (100 μM) was used as a positive control. The antiproliferative activity of WFA was inhibited in the presence of thiol donors; NAC (2.5 mM) and dithiothreitol (DTT) but not in the presence of trolox (G). Where indicated, data are presented as mean ± SD of 3 technical replicates. *p < 0.05.

Currently, the findings demonstrate that various combinations of PAC and WFA are highly synergistic against the proliferation of the human NSCLC cells, H1299, and A549.

Moreover, WFA was active against PAC-sensitive and PAC-resistant NSCLC cells thus demonstrating the potential therapeutic efficacy of WFA alone, and in combination with PAC against NSCLC cells and providing a strong rationale for further testing to advance this combination in clinical trials.

The Gupta/Aqil Research Team concluded in their Oncotarget Research Paper that Since cis-Pt alongside PAC is the current first-line chemotherapy for NSCLC without driver genetic mutations, they have shown that PAC with WFA is more potent and more efficacious than the standard of care.

More importantly, WFA was active against both drug-sensitive and drug-resistant cells which further broadens the scope and relevance of the PAC+WFA combination in NSCLC.

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DOI - https://doi.org/10.18632/oncotarget.27519

Full text - https://www.oncotarget.com/article/27519/text/

Correspondence to - Ramesh C. Gupta - rcgupta@louisville.edu and Farrukh Aqil - f0aqil01@louisville.edu

Keywords - non-small cell lung cancer, withaferin A, synergistic, combination index, paclitaxel

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