digitoxin and Liver-Neoplasms

Sorafenib is a chemotherapeutic agent approved for the treatment of hepatocellular carcinoma (HCC) in China. Digitoxin is a cardiotonic drug, which has been demonstrated to exhibit anticancer effects in a number of cancers, but not in HCC. The aim of the present study was to evaluate the combinational effect of sorafenib and digitoxin on the treatment of HCC and to investigate the relevant molecular mechanisms of action that underlie these effects. The proliferation, cell death and migration of HCC cell lines, HepG2 and BEL‑7402, were examined using MTT, acridine orange/ethidium bromide staining and scratch wound healing assays, respectively. In addition, alterations in the expression of phosphorylated-extracellular signal-regulated kinase (ERK), hypoxia‑inducible factor 1‑α (HIF‑1α), hypoxia‑inducible factor 2‑α (HIF‑2α) and vascular endothelial growth factor (VEGF) were measured prior to and following drug application using western blot analysis. Digitoxin and sorafenib synergistically inhibited cell viability, but did not inhibit migration, which was potentially mediated by suppression of ERK and hypoxia signaling. In downstream signaling pathways, the activity of ERK was synergistically suppressed by combinatorial treatment of HepG2 and BEL‑7402 cells with sorafenib and digitoxin. In addition, the expression of HIF‑1α, HIF‑2α and VEGF was synergistically downregulated by combinational treatment.

Topics: Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Hepatocellular; Cardiotonic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Digitoxin; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Sorafenib; Vascular Endothelial Growth Factor A

Hepatocellular carcinoma is the second deadliest cancer with limited treatment options. Loss of PTEN causes the P13K/Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer. Hence molecules targeting this pathway present good therapeutic strategies for liver cancer.. It was previously reported that Cardiac glycosides possessed antitumor activity by inducing apoptosis of multiple cancer cells through oxidative stress. However, whether Cardiac glycoside Lanatoside C can induce oxidative stress in liver cancer cells and induce cell death both in vitro and in vivo remains unknown.. Cell viability was measured by SRB assay. Cell death analysis was investigated by propidium iodide staining with flow cytometry and PARP cleavage. DCFH-DA staining and cytometry were used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Antitumor activity was investigated on mice xenografts in vivo.. In this study, we found that Cardiac glycosides, particularly Lanatoside C from Digitalis ferruginea could significantly inhibit PTEN protein adequate Huh7 and PTEN deficient Mahlavu human liver cancer cell proliferation by the induction of apoptosis and G2/M arrest in the cells. Lanatoside C was further shown to induce oxidative stress and alter ERK and Akt pathways. Consequently, JNK1 activation resulted in extrinsic apoptotic pathway stimulation in both cells while JNK2 activation involved in the inhibition of cell survival only in PTEN deficient cells. Furthermore, nude mice xenografts followed by MRI showed that Lanatoside C caused a significant decrease in the tumor size. In this study apoptosis induction by Lanatoside C was characterized through ROS altered ERK and Akt pathways in both PTEN adequate epithelial and deficient mesenchymal liver cancer cells.. The results indicated that Lanatoside C could be contemplated in liver cancer therapeutics, particularly in PTEN deficient tumors. This is due to Lanatoside C's stress inducing action on ERK and Akt pathways through differential activation of JNK1 and JNK2 by GSK3β.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Digitalis; Humans; Lanatosides; Liver Neoplasms; Mice; Mice, Nude; Oxidative Stress; PTEN Phosphohydrolase; Signal Transduction; Xenograft Model Antitumor Assays

Four cardenolide glycosides, glucodigifucoside (2), 3'-O-acetylglucoevatromonoside (9), digitoxigenin 3-O-β-D-glucopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 4)-3-O-acetyl-β-D-digitoxopyranoside (11), and purpureaglycoside A (12), isolated from the seeds of Digitalis purpurea, exhibited potent cytotoxicity against human renal adenocarcinoma cell line ACHN. These compounds exhibited significantly lower IC50 values against ACHN than that against normal human renal proximal tubule-derived cell line HK-2. In particular, 2 exhibited the most potent and carcinoma-specific cytotoxicity, with a sixfold lower IC50 value against ACHN than that against HK-2. Measurement of cyclin-dependent kinase inhibitor levels revealed that upregulation of p21/Cip1 expression was involved in the carcinoma-specific cytotoxicity of 2. Further, compound 2 also exhibited the carcinoma-specific cytotoxicity toward hepatocellular carcinoma cell line.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cardenolides; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Digitalis; Glycosides; Humans; Kidney Neoplasms; Liver Neoplasms; Seeds; Tumor Suppressor Protein p53; Up-Regulation

A 2-month-old female infant with congestive heart failure secondary to hepatic hemangiomatosis was treated with prednisone for five weeks without clinical improvement. She then underwent acute cardiac decompensation and required assisted ventilation. The hepatic artery was ligated to decrease the blood supply to the hemangiomata. Although the engorged liver softened dramatically, she continued to require mechanical ventilation for cardiac failure. Ten days postoperatively, she underwent digitalization with significant improvement in cardiac function, and she was then weaned from the respirator. Although, at 2 1/2 years of age, her liver has remained somewhat enlarged, her cardiovascular function has been normal. Our experience indicates that hepatic hemangiomatosis can be successfully treated via hepatic artery ligation and that cardiotonic measures might sometimes be required for recovery from coexisting congestive heart failure.

Topics: Angiomatosis; Digitalis; Female; Heart Failure; Hemangioma; Hepatic Artery; Humans; Infant; Ligation; Liver Neoplasms; Plants, Medicinal; Plants, Toxic; Skin Neoplasms