Lemongrass essential oil and citral inhibit Src/Stat3 activity and suppress the proliferation/survival of small-cell lung cancer cells, alone or in combination with chemotherapeutic agents

Maruoka,Takayuki; Kitanaka,Akira; Kubota,Yoshitsugu; Yamaoka,Genji; Kameda,Tomohiro; Imataki,Osamu; Dobashi,Hiroaki; Bandoh,Shuji; Kadowaki,Norimitsu; Tanaka,Terukazu

doi:10.3892/ijo.2018.4314

Lemongrass essential oil and citral inhibit Src/Stat3 activity and suppress the proliferation/survival of small-cell lung cancer cells, alone or in combination with chemotherapeutic agents

Authors:
- Takayuki Maruoka
- Akira Kitanaka
- Yoshitsugu Kubota
- Genji Yamaoka
- Tomohiro Kameda
- Osamu Imataki
- Hiroaki Dobashi
- Shuji Bandoh
- Norimitsu Kadowaki
- Terukazu Tanaka
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Affiliations: Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan, Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan, Department of Community Medicine, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan, Department of Laboratory Medicine, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
Published online on: March 13, 2018 https://doi.org/10.3892/ijo.2018.4314
Pages: 1738-1748

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Abstract

Small-cell lung cancer (SCLC) is intractable due to its high propensity for relapse. Novel agents are thus needed for SCLC treatment. Lemongrass essential oil (LG-EO) and its major constituent, citral, have been reported to inhibit the proliferation and survival of several types of cancer cells. However, the precise mechanisms through which LG-EO and citral exert their effects on SCLC cells have not been fully elucidated. SCLC cells express Src and have high levels of Src-tyrosine kinase (Src-TK) activity. In most SCLC cell lines, constitutive phosphorylation of Stat3(Y705), which is essential for its activation, has been detected. Src-TK can phosphorylate Stat3(Y705), and activated Stat3 promotes the expression of the anti-apoptotic factors Bcl-xL and Mcl-1. In the present study, LG-EO and citral prevented Src-TK from phosphorylating Stat3(Y705), resulting in decreased Bcl-xL and Mcl-1 expression, in turn suppressing the proliferation/survival of SCLC cells. To confirm these findings, the wild-type-src gene was transfected into the LU135 SCLC cell line (LU135‑wt-src), in which Src and activated phospho-Stat3(Y705) were overexpressed. The suppression of cell proliferation and the induction of apoptosis by treatment with LG-EO or citral were significantly attenuated in the LU135-wt-src cells compared with the control LU135-mock cells. The signal transducer and activator of transcription 3 (Stat3) signaling pathway is also associated with intrinsic drug resistance. LU135-wt-src cells were significantly resistant to conventional chemotherapeutic agents compared with LU135-mock cells. The combined effects of citral and each conventional chemotherapeutic agent on SCLC cells were also evaluated. The combination treatment exerted additive or more prominent effects on LU135-wt-src, LU165 and MN1112 cells, which are relatively chemoresistant SCLC cells. These findings suggest that either LG-EO or citral, alone or in combination with chemotherapeutic agents, may be a novel therapeutic option for SCLC patients.

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