Artemisia santolinifolia-Mediated Chemosensitization via Activation of Distinct Cell Death Modes and Suppression of STAT3/Survivin-Signaling Pathways in NSCLC.

Uyanga Batbold,Jun-Jen Liu

doi:10.3390/molecules26237200

Abstract

Conventional chemotherapy remains an integral part of lung cancer therapy, regardless of its toxicity and drug resistance. Consequently, the discovery of an alternative to conventional chemotherapy is critical. Artemisia santolinifolia ethanol extract (AS) was assessed for its chemosensitizer ability when combined with the conventional anticancer drug, docetaxel (DTX), against non-small cell lung cancer (NSCLC). SRB assay was used to determine cell viability for A549 and H23 cell lines. The potential for this combination was examined by the combination index (CI). Further cell death, analyses with Annexin V/7AAD double staining, and corresponding protein expressions were analyzed. Surprisingly, AS synergistically enhanced the cytotoxic effect of DTX by inducing apoptosis in H23 cells through the caspase-dependent pathway, whereas selectively increased necrotic cell population in A549 cells, following the decline in GPX4 level and reactive oxygen species (ROS) activation with the highest rate in the combination treatment group. Furthermore, our results highlight the chemosensitization ability of AS when combined with DTX. It was closely associated with synergistic inhibition of oncogenesis signaling molecule STAT3 in both cell lines and concurrently downregulating prosurvival protein Survivin. Conclusively, AS could enhance DTX-induced cancer cells apoptosis by abrogating substantial prosurvival proteins’ expressions and triggering two distinct cell death pathways. Our data also highlight that AS might serve as an adjunctive therapeutic option along with a conventional chemotherapeutic agent in the management of NSCLC patients.

Highlights

Conventional chemotherapy remains an integral part of lung cancer therapy, regardless of its toxicity and drug resistance
Our study demonstrated that Artemisia santolinifolia ethanol extract (AS) can be a promising chemosensitizer with the combination of conventional chemotherapeutic agent DTX for non-small cell lung cancer (NSCLC)
To elucidate whether the additive effect of AS on DTX-induced apoptosis was mediated by signal transducer and activator of transcription 3 (STAT3) signal transducer and downstream prosurvival protein, we evaluated the expression levels of STAT3, p-STAT3, and survivin in NSCLC cells after 48 h of drug exposure

Summary

Introduction

Conventional chemotherapy remains an integral part of lung cancer therapy, regardless of its toxicity and drug resistance. Artemisia santolinifolia ethanol extract (AS) was assessed for its chemosensitizer ability when combined with the conventional anticancer drug, docetaxel (DTX), against non-small cell lung cancer (NSCLC). AS synergistically enhanced the cytotoxic effect of DTX by inducing apoptosis in H23 cells through the caspase-dependent pathway, whereas selectively increased necrotic cell population in A549 cells, following the decline in GPX4 level and reactive oxygen species (ROS) activation with the highest rate in the combination treatment group. Our results highlight the chemosensitization ability of AS when combined with DTX. It was closely associated with synergistic inhibition of oncogenesis signaling molecule STAT3 in both cell lines and concurrently downregulating prosurvival protein Survivin. Lung cancer incidence declines twice in men in prevalence of women, the 5-year relative survival rate is still low, as patients diagnosed in late stage [3]

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