Costunolide, a Sesquiterpene Lactone, Suppresses Skin Cancer via Induction of Apoptosis and Blockage of Cell Proliferation

Abstract

Costunolide is a naturally occurring sesquiterpene lactone that demonstrates various therapeutic actions such as anti-oxidative, anti-inflammatory, and anti-cancer properties. Costunolide has recently emerged as a potential anti-cancer agent in various types of cancer, including colon, lung, and breast cancer. However, its mode of action in skin cancer remains unclear. To determine the anti-cancer potential of costunolide in skin cancer, human epidermoid carcinoma cell line A431 was treated with costunolide. A lactate dehydrogenase assay showed that costunolide diminished the viability of A431 cells. Apoptotic cells were detected by annexin V/propidium iodide double staining and Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay assay, and costunolide induced cell apoptosis via activation of caspase-3 as well as induction of poly-ADP ribose polymerase cleavage in A431 cells. In addition, costunolide elevated the level of the pro-apoptotic protein Bax while lowering the levels of anti-apoptotic proteins, including Bcl-2 and Bcl-xL. To address the inhibitory effect of costunolide on cell proliferation and survival, various signaling pathways, including mitogen-activated protein kinases, signal transducer and activator of transcription 3 (STAT3), nuclear factor κB (NF-κB), and Akt, were investigated. Costunolide activated the p38 and c-Jun N-terminal kinase pathways while suppressing the extracellular signal-regulated kinase (ERK), STAT3, NF-κB, and Akt pathways in A431 cells. Consequently, it was inferred that costunolide suppresses cell proliferation and survival via these signaling pathways. Taken together, our data clearly indicated that costunolide exerts anti-cancer activity in A431 cells by suppressing cell growth via inhibition of proliferation and promotion of apoptosis. Therefore, it may be employed as a potentially tumor-specific candidate in skin cancer treatment.

Back to the Roots—An Overview of the Chemical Composition and Bioactivity of Selected Root-Essential Oils

“…Moreover, COS has emerged as a potential tumor-specific candidate in skin cancer treatment. The anti-cancer activity of COS on human epidermoid carcinoma cells included the induction of apoptosis and suppression of cell proliferation and survival via various signaling pathways [ 288 ].…”

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“…[52][53][54] It is active against colorectal, cervical, hepatocellular, leukemia, breast, prostate, colon, gastric, melanoma, and lung cancer. [55,56]…”

Costunolide protects against alcohol‐induced liver injury by regulating gut microbiota, oxidative stress and attenuating inflammation in vivo and in vitro

“…Previous phytochemical investigations found that sesquiterpene lactones, lignans and volatile oil are the main constituents of D. souliei (Butturini et al, 2014; Tan, Jakupovic, Bohlmann, Jia, & Schuster, 1990). Especially, costunolide (cos) is considered as one of the main active sesquiterpene isolated from D. Souliei , which exerts varies pharmacological effects such as anti‐lung injury (Butturini et al, 2014), anti‐hepatitis B virus (Chen, Chou, Lee, Wang, & Yeh, 1995), anti‐ acute ulcerative colitis (Xie, Zhang, Zheng, & Shen, 2020), anti‐inflammatory (Park, Song, Kim, Park, & Kim, 2016), inhibiting alcohol‐induced gastric ulcer in mice (Zheng et al, 2016), and anti‐cancer effect (Fu et al, 2020; Lee, Cho, & Lim, 2021; Lin, Peng, & Su, 2015). Our previous study revealed that cos exerted protective activity against LPS/D‐GalN‐induced acute liver injury in mice via its anti‐inflammatory, anti‐oxidative and anti‐apoptotic capacities (Mao, Yi, Wang, Huang, & Chen, 2018).…”