Digitoxin activates EGR1 and synergizes with paclitaxel on human breast cancer cells

Einbond, Linda Saxe; Wu, Hui‐Lin; Su, Tao; Chang, T.-P.; Panjikaran, Maya; Wang, Xiaomei; Goldsberry, Sarah

doi:10.4103/1477-3163.72578

Cited by 19 publications

(26 citation statements)

References 20 publications

(27 reference statements)

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“…Figure 3 shows that DIG at 50 nM decreased the viability of lung tumorspheres by approximately about 60%. This is of clinical importance since the therapeutic plasma levels of DIG are considered to be in the ranges of 13 to 33 nM [ 33 , 34 ] and up to 46 nM [ 35 ]. Sox2, via the PI3K/AKT pathway, has been recently shown to be involved in resistance to conventional anticancer drugs such as Paclitaxel in prostate [ 36 ] and ovarian [ 37 ] cancers.…”

Section: Discussionmentioning

confidence: 99%

Formation of Tumorspheres with Increased Stemness without External Mitogens in a Lung Cancer Model

Yakisich

Azad

Venkatadri

et al. 2016

Stem Cells International

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Like with most solid tumors, the presence of a subpopulation of cancer stem cells (CSCs) or cancer stem-like cells (CS-LCs) has been associated with chemoresistance and tumor relapse in lung cancer cells. In the absence of serum, CSCs/CS-LCs have the ability to grow as lung tumorspheres (LTSs), and this system is routinely used for isolation and characterization of putative CSCs/CS-LCs. Methods to isolate LTSs are usually performed in serum-free media supplemented with specific additives such as epidermal growth factor and basic fibroblast growth factor. In this study, we report the generation of LTSs without the addition of any external mitogenic stimulation. LTSs generated in this manner demonstrated several traits usually associated with increased stemness such as elevated expression of the stemness-associated marker Sox2 and increased chemoresistance to conventional anticancer drugs. In addition, we report that the FDA-approved drug Digitoxin, at concentration close to its therapeutic level, decreased the viability of LTSs and downregulated Sox2 independent of the PI3K/AKT pathway. The potential use of LTSs generated without the addition of any external mitogenic stimulation to study the role of specific factor(s) associated with stemness properties is also discussed.

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Section: Discussionmentioning

confidence: 99%

Formation of Tumorspheres with Increased Stemness without External Mitogens in a Lung Cancer Model

Yakisich

Azad

Venkatadri

et al. 2016

Stem Cells International

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“…Co-treatment of cancer cells with Dig + PX has been explored in vitro in a few types of cancer. Studies in the MDA-MB-453 breast cancer cell line showed a synergistic antiproliferative effect with Dig concentrations as low as 13 nM ( 6 ). On the other hand, in the human prostate cancer cells (PC-3), Dig reversed both G 2 /M arrest and induction of apoptosis by PX ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

“…The combination index (CI) was calculated to investigate the combined effect of Dig or MonoD and PX. The CI was calculated using the following formula ( 6 ): CI = [IC 50 (CG + PX)/IC 50 (CG alone)] + [IC 50 (PX + CG)/IC 50 (PX alone)]. Where CG = Dig or MonoD and PX = paclitaxel.…”

Section: Methodsmentioning

confidence: 99%

“…Digitoxin (Dig) is an FDA approved drug for the treatment of cardiac disease. The therapeutic plasma levels of digitoxin is considered to be in the ranges of 13–33 nM ( 4 , 5 ) and up to 46 nM ( 6 ). Dig at micromolar concentrations inhibits the Na/K-ATPase, but it is believed that at nanomolar concentrations, it activates the Na + /K + -ATPase signalosome to transmit intracellular signals, leading to anticancer effects ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

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Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel

et al. 2015

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Despite significant advances in the understanding of lung cancer biology, the prognosis of cancer patients remains poor. Part of the failure of anticancer therapy is due to intratumoral heterogeneity in these patients that limits the efficacy of single agents. Therefore, there is an urgent need for new anticancer drugs or drug combination regimens that possess increased activity against all cellular subtypes found within the tumor. In this study, we evaluated the in vitro antiproliferative activity of the cardiac glycosides (CGs) digitoxin and its synthetic analog MonoD on H460 lung cancer cells grown under different culture conditions. The CGs were tested alone in H460 cells under routine culture as well as in cells growing under short (24–72 h) and prolonged serum starvation (7 days) in order to evaluate the activity of drugs on cancer cells under varied degrees of proliferation. Our results showed that both CGs, and MonoD in particular, have potent antiproliferative activity at clinically relevant concentrations against cells in all the tested culture conditions. In contrast, paclitaxel, hydroxyurea and colchicine were only active in cells growing in routine culture conditions, and relatively inactive in serum-starved conditions. Importantly, both CGs were able to potentiate the effect of clinically relevant concentrations of hydroxyurea or paclitaxel in serum-starved conditions. When paclitaxel was used in combination with CGs, the highest antiproliferative effect was obtained when paclitaxel was administered first, followed by either digitoxin or MonoD. Our results indicate that CGs have potential clinical applications in translational oncology especially in combination with other drugs, and warrants further investigation of CGs in more advanced preclinical models of lung cancer.

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“…This suggested that non‐toxic, therapeutic concentrations of digitalis may exert anti‐cancer effects. Consistent with this idea, the therapeutic plasma levels of Digitoxin of 13–33 nM (Kometiani et al, ; López‐Lázaro et al, ) and up to 46 nM (Einbond et al, ) exerts anti‐cancer activity in vitro. We recently demonstrated that Digitoxin and its synthetic derivative MonoD at therapeutic concentration (20–50 nM) can inhibits the viability of human H460 lung cancer cells growing under routine culture conditions (Yakisich et al, ,) as in cells with increased stemness properties such as lung tumorspheres (Yakisich et al, ,).…”

Section: Discussionmentioning

confidence: 80%

Anti‐Tumor Effects of Cardiac Glycosides on Human Lung Cancer Cells and Lung Tumorspheres

Kaushik

Yakisich

Azad

et al. 2017

Journal Cellular Physiology

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Lung cancer is a leading cause of cancer-related death in the United States. Although several drugs have been developed that target individual biomarkers, their success has been limited due to intrinsic or acquired resistance for the specific targets of such drugs. A more effective approach is to target multiple pathways that dictate cancer progression. Cardiac glycosides demonstrate such multimodal effects on cancer cell survival, and our aim was to evaluate the effect of two naturally occurring monosaccaridic cardiac glycosides-Convallatoxin and Peruvoside on lung cancer cells. Although both drugs had significant anti-proliferative effects on H460 and Calu-3 lung cancer cells, Convallatoxin demonstrated twofold higher activity as compared to Peruvoside using both viability and colony forming assays, suggesting a role for the aglycone region in dictating drug potency. The tumor suppressor p53 was found to be important for action of both drugs-p53-underexpressing cells were less sensitive as compared to p53-positive H460 cells. Further, assessment of p53-underexpressing H460 cells showed that drugs were able to arrest cells in the G0/G1 phase of the cell cycle in a dose-dependent manner. Both drugs significantly inhibited migration and invasion of cancer cells and decreased the viability of floating tumorspheres. An assessment of intracellular pathways indicated that both drugs were able to modulate proteins that are involved in apoptosis, autophagy, cell cycle, proliferation, and EMT. Our data suggest, a promising role for cardiac glycosides in lung cancer treatment, and provides impetus for further investigation of the anti-cancer potential of this class of drugs. J. Cell. Physiol. 232: 2497-2507, 2017. © 2016 Wiley Periodicals, Inc.

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Digitoxin activates EGR1 and synergizes with paclitaxel on human breast cancer cells

Cited by 19 publications

References 20 publications

Formation of Tumorspheres with Increased Stemness without External Mitogens in a Lung Cancer Model

Formation of Tumorspheres with Increased Stemness without External Mitogens in a Lung Cancer Model

Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel

Anti‐Tumor Effects of Cardiac Glycosides on Human Lung Cancer Cells and Lung Tumorspheres

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