Combination of 131I-trastuzumab and lanatoside C enhanced therapeutic efficacy in HER2 positive tumor model

Lanatoside C has a promising anti-tumor activity and is a potential candidate for radiosensitizers. In this study, we have investigated the therapeutic efficacy of the combination of 131I-trastuzumab and lanatoside C for inhibition of human epidermal growth factor receptor 2 (HER2) positive tumor progression in NCI-N87 xenograft model. The combination treatment (131I-trastuzumab and lanatoside C) showed highest cytotoxicity when compared to non-treated control or trastuzumab alone or 131I alone or 131I-trastuzumab alone in vitro. Biodistribution studies using 131I-trastuzumab or combination of 131I-trastuzumab and lanatoside C showed tumor uptake in BALB/c nude mice bearing HER2 positive NCI-N87 tumor xenograft model. The higher tumor uptake was observed in 131I-trastuzumab (19.40 ± 0.04% ID/g) than in the combination of 131I-trastuzumab and lanatoside C (14.02 ± 0.02% ID/g) at 24 h post-injection. Most importantly, an antitumor effect was observed in mice that received the combination of 131I-trastuzumab and lanatoside C (p = 0.009) when compared to control. In addition, mice received lanatoside C alone (p = 0.085) or 131I-trastuzumab alone (p = 0.160) did not significantly inhibit tumor progression compared with control. Taken together, our data suggest that combination of 131I-trastuzumab and lanatoside C might be a potential synergistic treatment for radioimmunotherapy to control the HER2 positive tumor.

Anticonvulsive potential of cardiac glycosides under conditions of pentilentetrazole-induced seizures in mice: comparative study

Aim. The research provides a comparative analysis of the possible anticonvulsant action of different cardiac glycosides, namely: digoxin, lanatoside C, strophanthin G and corglycone. In addition, it detrmines the leading medication among the abovementioned ones by dose-dependence of its anticonvulsant action. Material and Methods. The research was performed on 66 random-bred albino male mice. The anticonvulsant effect of cardiac glycosides was studied in a baseline model of pentylenetetrazole-induced seizures. The first series of experiment evaluated the effect of cardiac glycosides on the course of model seizures in comparable doses of approximately 1/10 LD50 for the corresponding drug: digoxin, lanatoside C and strophanthin G - at a dose of 0.8 mg/kg; corglycone - at a dose of 1 mg/kg. The second series of experiments used the drug-leader, which was digoxin, in a wide dose range from 0.2 to 1.6 mg/kg. Digoxin, strophanthin G and corglycone were administered subcutaneously for 15 minutes, lanatoside C - intragastrically for 30 minutes before the induction of experimental seizures. Convulsive agent - pentylenetetrazole in the form of an aqueous solution was administered to animals subcutaneously at a dose of 80 mg/kg. Results and Discussion. Digoxin at a dose of 0.8 mg/kg under conditions of pentylenetetrazole-induced seizures shows a pronounced anticonvulsant activity: it is the only one among the studied cardiac glycosides that probably reduces lethality. In addition, digoxin prolongs the latency period of the first attacks, and reduces the number of clonic-tonic paroxysms in 1 mouse. Moderate anticonvulsant properties of lanatoside C were found both by a statistically significant decrease in the number of clonic-tonic seizures in 1 mouse, and by a significant reduction in the duration of the convulsive period. Although strophanthin G is unlikely to affect lethality, it moderately reduces the severity of pentylenetetrazole-induced seizures in mice, as evidenced by a statistically significant prolongation of the latency period of the first seizures, as well as a decrease in the number of clonic-tonic seizures in 1 mouse and the duration of seizures. Prophylactic administration of corglycone only prolongs the latency period of seizures and significantly reduces the number of clonic-tonic seizures in 1 mouse. The results of the dose-dependence study of digoxin anticonvulsant action show a clear anticonvulsant potential of this cardiac glycoside in a wide range of doses - from 0.2 to 1.6 mg/kg - with a maximum effect at a dose of 0.8 mg/kg. Conclusions. It was found that cardiac glycosides have a different severity of anticonvulsant effect: the most powerful anticonvulsant effect is due to digoxin, lanatoside C and strophanthin G have moderate properties, and the least pronounced effect is characteristic to corglycone. In addition, it was determined that digoxin exhibits anticonvulsant properties in a wide range of doses, and has the most pronounced anticonvulsant effect at a dose of 0.8 mg/kg. The obtained results substantiate the expediency of further in-depth study of digoxin as an anticonvulsant medicine.

Combination of 131I-trastuzumab and lanatoside C enhanced therapeutic efficacy in HER2 positive tumor model

Lanatoside C has a promising anti-tumor activity and is a potential candidate for radiosensitizers. In this study, we have investigated the therapeutic efficacy of the combination of 131I-trastuzumab and lanatoside C for inhibition of human epidermal growth factor receptor 2 (HER2) positive tumor progression in NCI-N87 xenograft model. The combination treatment (131I-trastuzumab and lanatoside C) showed highest cytotoxicity when compared to non-treated control or trastuzumab alone or 131I alone or 131I-trastuzumab alone in vitro. Biodistribution studies using 131I-trastuzumab or combination of 131I-trastuzumab and lanatoside C showed tumor uptake in BALB/c nude mice bearing HER2 positive NCI-N87 tumor xenograft model. The higher tumor uptake was observed in 131I-trastuzumab (19.40±0.04% ID/g) than in the combination of 131I-trastuzumab and lanatoside C (14.02±0.02% ID/g) at 24 hours post-injection. Most importantly, an antitumor effect was observed in mice that received the combination of 131I-trastuzumab and lanatoside C (p=0.009) when compared to control. In addition, mice received lanatoside C alone (p=0.085) or 131I-trastuzumab alone (p=0.160) did not significantly inhibit tumor progression compared with control. Taken together, our data suggest that combination of 131I-trastuzumab and lanatoside C might be a potential synergistic treatment for radioimmunotherapy to control the HER2 positive tumor.

Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways

Cardiac glycosides (CGs) are a diverse family of naturally derived compounds having a steroid and glycone moiety in their structures. CG molecules inhibit the α-subunit of ubiquitous transmembrane protein Na+/K+-ATPase and are clinically approved for the treatment of cardiovascular diseases. Recently, the CGs were found to exhibit selective cytotoxic effects against cancer cells, raising interest in their use as anti-cancer molecules. In this current study, we explored the underlying mechanism responsible for the anti-cancer activity of Lanatoside C against breast (MCF-7), lung (A549), and liver (HepG2) cancer cell lines. Using Real-time PCR, western blot, and immunofluorescence studies, we observed that (i) Lanatoside C inhibited cell proliferation and induced apoptosis in cell-specific and dose-dependent manner only in cancer cell lines; (ii) Lanatoside C exerts its anti-cancer activity by arresting the G2/M phase of cell cycle by blocking MAPK/Wnt/PAM signaling pathways; (iii) it induces apoptosis by inducing DNA damage and inhibiting PI3K/AKT/mTOR signaling pathways; and finally, (iv) molecular docking analysis shows significant evidence on the binding sites of Lanatoside C with various key signaling proteins ranging from cell survival to cell death. Our studies provide a novel molecular insight of anti-cancer activities of Lanatoside C in human cancer cells.