Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs

Abstract

Plantaginaceae, a popular traditional Chinese medicine, has long been used for treating various diseases from common cold to cancer. Linalool is one of the biologically active compounds that can be isolated from Plantaginaceae. Most of the commonly used cytotoxic anticancer drugs have been shown to induce apoptosis in susceptible tumor cells. However, the signaling pathway for apoptosis remains undefined. In this study, the cytotoxic effect of linalool on human cancer cell lines was investigated. Water-soluble tetrazolium salts (WST-1) based colorimetric cellular cytotoxicity assay, was used to test the cytotoxic ability of linalool against U937 and HeLa cells, and flow cytometry (FCM) and genechip analysis were used to investigate the possible mechanism of apoptosis. These results demonstrated that linalool exhibited a good cytotoxic effect on U937 and HeLa cells, with the IC50 value of 2.59 and 11.02 μM, respectively, compared with 5-FU with values of 4.86 and 12.31 μM, respectively. After treating U937 cells with linalool for 6 h, we found an increased sub-G1 peak and a dose-dependent phenomenon, whereby these cells were arrested at the G0/G1 phase. Furthermore, by using genechip analysis, we observed that linalool can promote p53, p21, p27, p16, and p18 gene expression. Therefore, this study verified that linalool can arrest the cell cycle of U937 cells at the G0/G1 phase and can arrest the cell cycle of HeLa cells at the G2/M phase. Its mechanism facilitates the expression of the cyclin-dependent kinases inhibitors (CDKIs) p53, p21, p27, p16, and p18, as well as the non-expression of cyclin-dependent kinases (CDKs) activity.

Casticin induces apoptosis and G0/G1 cell cycle arrest in gallbladder cancer cells

“…4d). A recent study identified p27 as an important cyclin-dependent kinase inhibitor that inhibits the activation of cyclin D-CDK4 complexes and induces cell cycle arrest at the G0/G1 and G2/M phases [18]. In addition, Akt pathway regulates cell cycle progression and cell proliferation by influencing p27, and the results presented in Fig.…”

The impact of compounds isolated from Ocimum sp. on apoptotic activity of osteoclast

“…Moreover, it has been demonstrated that linalool can induce the cell cycle of U937 cells to arrest at the G0/G1 phase, while HeLa cells arrest at the G2/M phase, and its function facilitates the expression of p53, p21, p27, p16 and p18 (CDKIs) and the non-expression of CDK activity (Chang et al, 2015). Therefore, linalool can inhibit the cell cycle of leukemia cells and cervical cancer cells, and it could thus be used to arrest cell cycle of osteoclast and to develop novel therapeutic agents for periodontal disease.…”

Kazakh Ziziphora Species as Sources of Bioactive Substances

“…bungeana [201] trans-Sabinene hydrate (64) Z. clinopodioides subsp. rigida (0.1%) [21] Antiviral (HSV-1) [282] Moderate repellent (against tick Amblyomma americanum) [305] Z. tenuior [94] Anti-inflammatory (in carrageenan-induced edema and inhibition of hyperalgesia induced by L-glutamate and prostaglandin E2 in rats) [311]; anti-inflammatory (through inhibition of the expression of TNF-α and IL-6 in LPS-stimulated RAW 264.7 cells) [312]; antiinflammatory (in cigarette smoke-induced ALI in mice through inhibiting NF-κB activation) [313] Cytotoxic (human amelanotic melanoma cell line C32, renal cell adenocarcinoma ACHN, hormone-dependent prostate carcinoma LNCaP) [314]; induction of apoptosis (variety of human leukaemia cells) [315][316][317] Hypocholesterolemic (through inhibition of HMG-CoA reductase and conversion of lanosterol to cholesterol) [318,319] Protective effect against t-BOOH induced mutagenesis [194] Review on some effects on cardiovascular system [221] Sedative and anxiolytic [320]; antidepressant [321]; GABAA receptor modulation [322] OH Z. clinopodioides subsp. rigida [21] Z. tenuior [94] p-Menth-3-en-8-ol (65)…”

“…rigida [21] Z. clinopodioides subsp. rigida (12.5%) [21] Z. tenuior (53.97%) [179] Linalool ( Anti-inflammatory (in carrageenan-induced edema and inhibition of hyperalgesia induced by L-glutamate and prostaglandin E 2 in rats) [311]; anti-inflammatory (through inhibition of the expression of TNF-α and IL-6 in LPS-stimulated RAW 264.7 cells) [312]; anti-inflammatory (in cigarette smoke-induced ALI in mice through inhibiting NF-κB activation) [313] Cytotoxic (human amelanotic melanoma cell line C32, renal cell adenocarcinoma ACHN, hormone-dependent prostate carcinoma LNCaP) [314]; induction of apoptosis (variety of human leukaemia cells) [315][316][317] Hypocholesterolemic (through inhibition of HMG-CoA reductase and conversion of lanosterol to cholesterol) [318,319] Protective effect against t-BOOH induced mutagenesis [194] Review on some effects on cardiovascular system [221] Sedative and anxiolytic [320]; antidepressant [321]; GABA A receptor modulation [322] Analgesic activity reviewed [199] Review on metabolism and toxicity [200] Molecules 2016, 21, 826 20 of 53 [296]; antioxidant [273,[297][298][299] Review on some effects on cardiovascular system [221] Gastroprotective effects in the acute and chronic ulcer models in rats [300] Positive allosteric modulator of the GABAA receptors in primary cultures of mouse cortical neurons [301] Anti-hyperglycemic and anti-hyperlipidemic activity in high fat-induced type 2 diabetic C57BL/6J mice [302] and protective effect in nephropathy [303] Analgesic activity reviewed [199] Review on metabolism and toxicity [200]; general review on thyme and 62 [304] cis-Sabinene hydrate …”