Investigation of the cytotoxic activity of two novel digitoxigenin analogues on H460 lung cancer cells

Abstract

Cardiac glycosides (CGs) are natural compounds traditionally used for the treatment of heart disorders, and recently new therapeutic possibilities were proposed. Their antitumor reports and clinical trials have notably enhanced, including those targeted for lung cancer, the most lethal type that lacks of new treatment agents, instigating the research of these molecules. The CGs studied here, named C10 {3β-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin} and C18 (3β-(aminoacetyl)amino-3-deoxydigitoxigenin), are semisynthetic derivatives prepared from digitoxigenin scaffold. Both compounds demonstrated high cytotoxicity for different cancer cell lines, especially H460 lung cancer cells, and their cytotoxic effects were deeply investigated using different methodological approaches. C10 induced cell death at lower concentrations and during shorter periods of treatment than C18, and increased the number of small and irregular nuclei, which are characteristics of apoptosis. This type of cell death was confirmed by caspase-3/7 assay. Both compounds reduced H460 cells proliferative potential by long-term action, and C10 showed the strongest potential. Moreover, these compounds induced a significant decrease of the area and viability of H460 spheroids providing preclinical favorable profiles to develop new chemotherapeutic agents.

Cardiac Glycosides from African Medicinal Plants as Promising Therapeutics

“…Even clinical trials for the treatment of cancer have begun using some cardiac glycosides or their derivatives. 15,44 Anvirzel, a water extract from oleander, was the first cardiac glycoside examined in an anticancer clinical study and showed substantial anticancer action against a variety of malignancies with few side effects. [45][46][47] Cardiac glycosides isolated from Thevetia peruviana (Pers.)…”

“…All cardiac glycosides contain a steroid ring connected to an unsaturated lactone ring in position 17, and many of them are related to a sugar moiety in position 3 as well. 15,16 This review on cardiac glycosides isolated from the African region will help broaden the scope of the importance of this secondary metabolite. It will also encourage further research into their isolation with great pharmacological activities, leading to drug discovery and development in Africa.…”

Emergence of Cardiac Glycosides as Potential Drugs: Current and Future Scope for Cancer Therapeutics

“…Besides, these compounds induced autophagic cell death by attenuating the PI3K/AKT/mTOR signaling pathway through the inhibition of mTOR, LC3, Beclin 1, PI3K, and p62 genes [ 15 , 126 , 127 ]. Recently, Boff et al [ 143 ] demonstrated the cytotoxic effect of semisynthetic C10 and C18 digitoxigenin analogs on H460 lung cancer cells. Both the compounds demonstrated high cytotoxicity as they induced apoptotic activity and reduced the cellular viability of H460 cells.…”

Inhibitory Effects of Digoxin and Digitoxin on Cell Growth in Human Ovarian Cancer Cell Line SKOV-3

“…8 CGs also inhibit testosterone production via the attenuation of cAMP accumulation, activities of adenylyl cyclase and cytochrome P450 scc in rat testicular cells [9][10][11] and progesterone release by rat granulosa cells via a Na + , K + -ATPaseindependent mechanism involving the inhibition of post-cAMP pathway cytochrome P450 scc and the protein function of steroidogenic acute regulatory (StAR) protein. 12 CGs have been known to possess anticancer effects in endocrine-related cancers comprising lung cancer, 13 prostate cancer, [14][15][16][17] and breast cancer 18 through inhibiting the cell migration 19 and proliferation and inducing apoptosis. 20,21 CG induces cell apoptosis in MCF-7 (estrogen receptor positive-breast cancer cell line) and MDA-MB-468 (triplenegative breast cancer) through arresting the G 0 /G 1 phase.…”