Tomentosin Induces Telomere Shortening and Caspase‐Dependant Apoptosis in Cervical Cancer Cells

Abstract

Tomentosin, a natural sesquiterpene lactone purified from of Inula viscosa L., was investigated for its anti-proliferative, telomere shortening, and apoptotic effects on human cervical cancer HeLa and SiHa cell lines. Tomentosin was found to inhibit the growth of SiHa and HeLa cell lines in dose and time-dependent manner (IC values of 7.10 ± 0.78 μM and 5.87 ± 0.36 μM, respectively after 96 h of treatment). As evidenced by TTAGGG telomere length assay, tomentosin target specifically the telomeric overhang lengthening. This was confirmed by the evaluation of the cytotoxic effects of tomentosin in the foetal fibroblast Wi38 and JW10 cells which were derived from Wi38 and express hTERT, the telomerase catalytic subunit. We found that JW10 cells are 4.7-fold more sensitive to tomentosin which argues for telomere as its specific target. Furthermore, we found that tomentosin mediate this cytotoxic effect by inducing apoptosis and cell cycle arrest at G2/M phase. Morphological features of treated cells, as evidenced by Hoechst 33324 staining, revealed that the cytotoxic effect was due to induction of apoptosis. This was accompanied by pro-caspase-3 cleavage, an increase in caspase-3 activity and a cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, tomentosin induced a decrease in mitochondrial membrane potential (ΔΨm) and an increase in reactive oxygen species (ROS), accompanied by a decrease in Bcl-2 expression. This indicates that tomentosin-induced apoptosis may involve a mitochondria-mediated signaling pathway. This study provides the first evidence that tomentosin targets telomere machinery and induces apoptosis in cervical cancer cells. The molecular mechanism underlying tomentosin-induced apoptosis may involve a mitochondria-mediated signaling pathway. J. Cell. Biochem. 118: 1689-1698, 2017. © 2016 Wiley Periodicals, Inc.

CDC5L Promotes hTERT Expression and Colorectal Tumor Growth

“…The presence of telomerase in more than 80% of human cancer cells indicates that the enzyme may be a promising target for cancer therapy. Telomerase inhibitors are likely to kill cancer cells by inducing senescence or apoptosis through telomere shortening, and many different classes of anti-cancer compounds that directly inhibit telomerase have been developed [36]. Most studies have shown that telomeres have unequal lengths in tumors compared with normal tissues [37].…”

Tomentosin Displays Anti-Carcinogenic Effect in Human Osteosarcoma MG-63 Cells via the Induction of Intracellular Reactive Oxygen Species

“…Tomentosin is a natural compound extracted from I. viscosa L. and it is recognized as an effective therapeutic agent against various cancers [9]. However, the anti-carcinogenic effects of tomentosin on many kinds of cancer have not been studied so far.…”

“…In modern medicine, natural compounds have been a crucial source of many drugs. Tomentosin is a sesquiterpene lactone isolated from Inula viscosa (L.) Aiton., which is widely used as a medicine because it exhibits essential therapeutic properties, such as anti-inflammatory [7], anti-bacterial, and anti-cancer activities [8,9]. Moreover, recent research has shown that tomentosin has an anti-proliferative effect on human cancer cell lines in vitro.…”

“…Moreover, recent research has shown that tomentosin has an anti-proliferative effect on human cancer cell lines in vitro. Tomentosin also induces apoptosis via telomere shortening in human cervical cancer cells [9].…”

The Telomerase and Alternative Lengthening of Telomeres Mechanisms Regulate Laryngeal Cancer Cell Apoptosis via the PI3K/Akt Pathway

“…The role of apoptosis in the antitumor effects of telomere-shortening has been acknowledged in various cancers, including cervical cancer and Epstein-Barr virus (EBV)-positive B lymphocytes [10][11][12]. However, whether apoptosis is involved in the antitumor effects of the silencing of telomerase and ALT in LSCC have not been elucidated.…”