Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
College of Pharmacy, Chonnam National University, Gwangju 61186, Korea.
Int J Mol Sci. 2021 Feb 19;22(4):2075. doi: 10.3390/ijms22042075.
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.
寇斯特酮内酯是一种天然存在的倍半萜内酯，具有多种治疗作用，如抗氧化、抗炎和抗癌特性。寇斯特酮内酯最近成为各种类型癌症（包括结肠癌、肺癌和乳腺癌）的潜在抗癌药物。然而，其在皮肤癌中的作用机制尚不清楚。为了确定寇斯特酮内酯在皮肤癌中的抗癌潜力，用人表皮癌细胞系 A431 处理寇斯特酮内酯。乳酸脱氢酶测定表明寇斯特酮内酯降低了 A431 细胞的活力。通过 Annexin V/碘化丙啶双重染色和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记测定检测凋亡细胞，寇斯特酮内酯通过激活 caspase-3 以及诱导 A431 细胞中多聚 ADP 核糖聚合酶裂解诱导细胞凋亡。此外，寇斯特酮内酯升高了促凋亡蛋白 Bax 的水平，同时降低了抗凋亡蛋白 Bcl-2 和 Bcl-xL 的水平。为了研究寇斯特酮内酯对细胞增殖和存活的抑制作用，研究了各种信号通路，包括丝裂原活化蛋白激酶、信号转导和转录激活因子 3（STAT3）、核因子 κB（NF-κB）和 Akt。寇斯特酮内酯激活了 p38 和 c-Jun N-末端激酶途径，同时抑制了 A431 细胞中的细胞外信号调节激酶（ERK）、STAT3、NF-κB 和 Akt 途径。因此，可以推断寇斯特酮内酯通过抑制增殖和促进凋亡来抑制这些信号通路来抑制细胞增殖和存活。总之，我们的数据清楚地表明，寇斯特酮内酯通过抑制增殖和促进凋亡来抑制细胞生长，从而在 A431 细胞中发挥抗癌活性。因此，它可能被用作皮肤癌治疗中具有潜在肿瘤特异性的候选药物。
