Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1α and STAT3 in KRAS mutant human colon cancer cells

Mi, Chunliu; Cao, Xiang-Xiang; Ma, Kai; Wei, Mian; Xu, Wenjing; Lin, Yan; Zhang, Jihong; Wang, Tianyun

doi:10.1016/j.cbi.2021.109729

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…Digitoxin has fatal effects on cell viability and it induced apoptosis to different degrees in the four pancreatic cancer cell lines examined in this study. These results are in accordance with previous studies using cardiac glycosides in human glioma and pancreatic cancer cell lines [ 49 , 50 ]. In an earlier study, we found intracellular calcium was significantly increased in the cell lines BxPC-3 (120%), CFPAC-1 (117%), and Panc-1 (160%) treated with digitoxin at therapeutic concentrations of 25–40 nM.…”

Section: Discussionsupporting

confidence: 93%

Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype

Lindholm

Ejeskär

Szekeres

2022

IJMS

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Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1–100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.

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Section: Discussionsupporting

confidence: 93%

Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype

Lindholm

Ejeskär

Szekeres

2022

IJMS

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“…Astragaloside A can inhibit the progression of colorectal cancer cells and inhibit the migration and EMT progression of cervical cancer cells . Digitoxin has an inhibitory effect on pancreatic cancer cells and can reduce HIF-1α and STAT3 to promote apoptosis and inhibit the proliferation and migration of KRAS mutant human colon cancer cells . However, the effects of these active ingredients on thyroid cancer, especially undifferentiated thyroid cancer, have not yet been reported.…”

Section: Discussionmentioning

confidence: 99%

“… 56 Digitoxin has an inhibitory effect on pancreatic cancer cells 57 and can reduce HIF-1α and STAT3 to promote apoptosis and inhibit the proliferation and migration of KRAS mutant human colon cancer cells. 58 However, the effects of these active ingredients on thyroid cancer, especially undifferentiated thyroid cancer, have not yet been reported. Our study verified the anti-ATC effects of the active ingredients of digitalis through network pharmacology, molecular docking, and preliminary experiments.…”

Section: Discussionmentioning

confidence: 99%

Incorporating Network Pharmacology and Experimental Validation to Identify Bioactive Compounds and Potential Mechanisms of Digitalis in Treating Anaplastic Thyroid Cancer

Zhu,

Liang,

Guo

et al. 2024

ACS Omega

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Anaplastic thyroid cancer (ATC) is one of the most lethal malignant tumors for which there is no effective treatment. There are an increasing number of studies on herbal medicine for treating malignant tumors, and the classic botanical medicine Digitalis and its active ingredients for treating heart failure and arrhythmias have been revealed to have significant antitumor efficacy against a wide range of malignant tumors. However, the main components of Digitalis and the molecular mechanisms of its anti-ATC effects have not been extensively studied. Here, we screened the main components and core targets of Digitalis and verified the relationship between the active components and targets through network pharmacology, molecular docking, and experimental validation. These experiments showed that the active ingredients of Digitalis inhibit ATC cell activity and lead to ATC cell death through the apoptotic pathway.

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“…The digitoxin, famous as cardiotonic steroids, rescued HUVEC migration and loop formation that macrophages induced and also arrested SKOV3 cell growth and migration under macrophage conditioned media ( Trenti et al, 2018 ; Whayne, 2018 ; Bejček et al, 2021 ). It also weakened HIF-1α protein expression by suppressing the phosphorylation of ribosomal protein S6 kinase (p70S6K) and eIF4E binding protein-1 (4E-BP1) in colon cancer cells ( Mi et al, 2022 ). Significantly, luteolin enabled inhibition of angiogenesis induction of M2-like TAMs, achieved by the downregulation of HIF-1α and STAT3 signaling ( Fang et al, 2018 ).…”

Section: Co-regulating Tumor Angiogenesis and Tme By Tcmmentioning

confidence: 99%

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

et al. 2022

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Tumor angiogenesis is one of the most important processes of cancer deterioration via nurturing an immunosuppressive tumor environment (TME). Targeting tumor angiogenesis has been widely accepted as a cancer intervention approach, which is also synergistically associated with immune therapy. However, drug resistance is the biggest challenge of anti-angiogenesis therapy, which affects the outcomes of anti-angiogeneic agents, and even combined with immunotherapy. Here, emerging targets and representative candidate molecules from ethnopharmacology (including traditional Chinese medicine, TCM) have been focused, and they have been proved to regulate tumor angiogenesis. Further investigations on derivatives and delivery systems of these molecules will provide a comprehensive landscape in preclinical studies. More importantly, the molecule library of ethnopharmacology meets the viability for targeting angiogenesis and TME simultaneously, which is attributed to the pleiotropy of pro-angiogenic factors (such as VEGF) toward cancer cells, endothelial cells, and immune cells. We primarily shed light on the potentiality of ethnopharmacology against tumor angiogenesis, particularly TCM. More research studies concerning the crosstalk between angiogenesis and TME remodeling from the perspective of botanical medicine are awaited.

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Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1α and STAT3 in KRAS mutant human colon cancer cells

Cited by 10 publications

References 31 publications

Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype

Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype

Incorporating Network Pharmacology and Experimental Validation to Identify Bioactive Compounds and Potential Mechanisms of Digitalis in Treating Anaplastic Thyroid Cancer

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

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