Convallatoxin, a Dual Inducer of Autophagy and Apoptosis, Inhibits Angiogenesis In Vitro and In Vivo

Abstract

Autophagy and apoptosis are important processes that control cellular homeostasis and have been highlighted as promising targets for novel cancer therapies. Here, we identified convallatoxin (CNT), isolated from Antiaris toxicaria, as a dual inducer of autophagy and apoptosis. CNT exerts cytotoxic effects on a number of cancer and normal cell lines and induces apoptosis by increasing caspase-3 and poly ADP ribose polymerase (PARP) cleavage. Moreover, dose- and time-dependent autophagic activity was detected in CNT-treated cells, and mammalian target of rapamycin (mTOR)/p70S6K signal pathway inhibition was observed. Notably, CNT inhibits human umbilical vein endothelial cell (HUVEC) growth and exerts anti-angiogenic activity in vitro and in vivo. Collectively, these results demonstrate that the naturally occurring compound, CNT, is a novel anti-angiogenic compound via dual inducing of autophagy and apoptosis.

PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells

“…This modified form, termed LC3B-II, is involved in the elongation of the phagophore. 28 However, LC3B-II is also degraded inside the lysosomes or deconjugated by ATG4. 29 Therefore, in order to measure autophagic flux, through 3-AWA (subtoxic doses)-induced autophagy, the LysoTraker Green dye was employed to characterize acidic spherical organelles formed at the onset of autophagy.…”

Cyclopalladated Compound 7a Induces Apoptosis- and Autophagy-Like Mechanisms in Paracoccidioides and Is a Candidate for Paracoccidioidomycosis Treatment

“…It is not the first time that both apoptosis and autophagy have been induced by the same compound. The simultaneous induction of these processes has been reported, e.g., for a curcumin analog against hepatocellular carcinoma cells (27) and by convallatoxin, an angiogenesis inhibitor (28). This is the first time programmed cell death has been shown to occur in Paracoccidioides; however, it has already been described in other unicellular organisms, including yeast cells and bacteria (29,30).…”

Inhibition of cell proliferation, invasion and migration by the cardenolides digitoxigenin monodigitoxoside and convallatoxin in human lung cancer cell line

“…(Braga et al 1996) was evaluated for the first time in this study. CON, isolated from Convallaria majalis L., has been reported to possess cytotoxic effects against several cancer cells (Juncker et al 2011;Yang et al 2014). In order to investigate the cytotoxic effects of these compounds in other cancer cells, human non-small cell lung cancer (NSCLC, A549), human rhabdomyosarcoma RD, human colon carcinoma HCT-8 and human prostate carcinoma LNcAP cell lines were selected.…”

“…In A549 cell line, the most sensitive cell line for both compounds, the IC 50 values were 12.34 and 11.03 nM, respectively, after 48 h. CON was identified as a potent cardenolide in different reports, with IC 50 values at nM concentrations, as herein observed. Its anti-proliferative effects were evaluated in colorectal cancer (HT29, HCT116 and CC20) (Felth et al 2009), non-small cell lung cancer (NIH-H460 and A549) (Liu, Tang, et al 2013;Yang et al 2014), glioblastoma (U87MG), cervical cancer (HeLa), liver carcinoma (HepG2) and fibrosarcoma (HT1080) (Yang et al 2014) human cell lines. It was also shown that CON caused a dual induction of apoptosis and autophagy in HeLa cells (Yang et al 2014).…”

“…Additionally, cardenolides such as ouabain have been reported to reduce the migration and invasive characteristics of some cancer cell lines (Pongrakhananon et al 2013). However, only a few studies have evaluated the migration and invasion potential of cardenolides by in vitro assays (Klausmeyer et al 2009;Pongrakhananon et al 2013;Yang et al 2014). Thus, further studies are needed, to elucidate their metastatic potential.…”