hydroxysafflor-yellow-a and Liver-Neoplasms

Hydroxysafflor yellow A (HSYA) extracted from the herb Cathartics tinctorius L. negatively regulates liver cancer growth. However, the exact mechanism of HSYA action in liver cancer remains largely unknown. In this study, HSYA inhibited liver cancer cell growth in vivo and in vitro, evidenced by cell proliferation inhibition detected by CCK8, numerous apoptotic cells shown by flow cytometry assay, and expression of apoptosis-related proteins determined by western blot. Importantly, our data revealed that HSYA triggered autophagic response and autophagosome accumulation considering the increased levels of LC3II-conversion examined by western blot, LC3 puncta visualized by immunofluorescence, and expression of autophagy-related genes shown by quantitative real-time PCR. Furthermore, HSYA blocked the late-phase of autophagic flux via impairing the lysosomal acidification and downregulating LAMP1 expression, thereby likely inducing apoptosis. In addition, HSYA inhibited PI3K/AKT/mTOR signaling pathway. Taken together, as HSYA might inhibit cell proliferation and promote apoptosis via blocking autophagic flux in liver cancer, it may be considered a promising candidate for liver cancer therapy.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagosomes; Autophagy; Cell Proliferation; Chalcone; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Liver Neoplasms; Lysosomes; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Quinones; Signal Transduction; TOR Serine-Threonine Kinases

The antitumor effect of hydroxysafflor yellow A (HSYA), an active ingredient of the herb Carthamus tinctorius L. (Asteraceae) (safflower), was investigated in the current work. Researches of HSYA on vasculogenesis inhibition, along with the related molecular mechanisms, including the expression of MMP-2, MMP-9, and p38MAPK (COX-2, ATF-2, p-p38MAPK, and p38MAPK) signaling pathway in H22 tumor-bearing mice or HepG2 cells were performed. The animal experiments proved the level of MMP-2 and MMP-9 in H22-transplanted tumor tissue in mice markedly decreased by HSYA, and results both in vivo and in vitro confirmed that COX-2 expression was reduced significantly via p38MAPK|ATF-2 signaling pathway. According to the outcomes, HSYA suppressed p38MAPK phosphorylation in a concentration-dependent manner, while exerting no effect on the total p38MAPK protein expression. It was also showed that suppression of p38 activation by SB203580 decreased the HepG2 cell viability, proliferation, and migration, wherein HSYA exhibited a similar effect. Furthermore, Western blot analysis on caspase-3 and cleaved-caspase-3 revealed that HSYA could induce apoptosis of HepG2 cells. These findings provided experimental evidences that HSYA might be a promising anticancer agent for HCC.

Topics: Animals; Carcinoma, Hepatocellular; Chalcone; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hep G2 Cells; Humans; Liver Neoplasms; Male; Mice; Neovascularization, Pathologic; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pigments, Biological; Quinones

Liver cancer is the second leading cause of cancer death. Due to treatments failures from drug resistance and cancer metastasis, discovering more effective treatments is imperative. As an angiogenesis inhibitor extracted from the Chinese herb-Safflower, hydroxysafflor yellow A (HSYA) inhibits the tumor growth in H22-bearing mice. Poorly differentiated hepatoma cells showed the ability to invade and metastasize, which are dependent on the angiogenesis. Accordingly, we hypothesized that HSYA could inhibit the metastasis of liver cancer cells. We investigated the metastasizing potential of human hepatic carcinoma SMMC-7721 cells treated with HSYA. A pulmonary metastatic model of mouse hepatoma H22 cells was established to evaluate the effect and possible mechanism of HSYA on lung metastasis from liver cancer. The results showed that HSYA inhibited the proliferation, invasion and migration of SMMC-7721 cells and reduced its adhesion to the extracellular matrix (ECM). In H22 mice treated with HSYA, the formation of E-cadherin/β-catenin complex resulted in the activation of peroxisome proliferator-activated receptor γ and inhibition of matrix metalloproteinase-2. As a result, the degradation of ECM was reduced and epithelial-mesenchymal transition was prevented. The present findings indicate that HSYA can prevent pulmonary metastasis in liver cancer, which provides strong evidence for the application of HSYA in treatments.

Topics: Animals; beta Catenin; Cadherins; Carcinoma, Hepatocellular; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Survival; Chalcone; Humans; Liver Neoplasms; Lung Neoplasms; Male; Mice; Quinones

Hydroxysafflor yellow A (HSYA), a flavonoid derived and isolated from traditional Chinese medicine Carthamus tinctorius L., possesses anti-tumor activity. However, its effects on hepatocellular carcinoma (HCC) have not been investigated. The proliferation and metastasis of HCC are dependent on angiogenesis, which also strongly links with several signal transduction pathways associated with cell proliferation and apoptosis. This study aimed to explore the effect of HSYA on vasculogenesis and to determine its molecular mechanism by investigating the expression of ERK/MAPK (p-c-Raf, c-Raf, p-ERK1/2, ERK1/2) and NF-κB (p65, IκB and p-IκB) signaling pathway in H22 tumor-bearing mice. The results showed that HSYA could considerably suppress tumor growth by inhibiting secretion of angiogenesis factors (vascular endothelial growth factor A, basic fibroblast growth factor) and vascular endothelial growth factor receptor1. At the moleculcould block ERK1/2 phosphorylation and then restrain the activation of NF-κB and its nuclear translocation by down-regulating the expression of p65 in the nucleus, up-regulating p65 level in the cytoplasm, inhibiting IκB phosphorylation and cytoplasmic degradation of IκB-α. Finally, we demonstrate that HSYA could suppress mRNA expression levels of cell proliferation-related genes (cyclinD1, c-myc, c-Fos) compared with negative control group. And best of all, HSYA could improve spleen/thymus indexes, which was evaluated as the marker of protective effect on the immune system. Our findings support HSYA as a promising candidate for the prevention and treatment of HCC.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Chalcone; Liver Neoplasms; Male; MAP Kinase Signaling System; Mice; Neoplasm Transplantation; Neovascularization, Pathologic; NF-kappa B; Quinones