Shikonin, a major ingredient in the Chinese traditional herb Lithospermum erythrorhixon, exhibits multiple biological functions including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we delineated the molecular mechanisms of shikonin in the apoptosis of 143B osteosarcoma cells. Shikonin reduced the cell viability of 143B cells in a dose-and time-dependent manner. The IC 50 at 24 h and 48 h for 143B cells was 4.55 and 2.01 m mM, respectively. A significantly elicited hypodiploid cell population was found in cells treated with 2, 4, and 8 m mM shikonin for 24 h. Moreover, treatment with shikonin induced reactive oxygen species (ROS) generation, increased extracellular signal-regulated kinase (ERK) phosphorylation, decreased B-cell lymphoma-2 (Bcl2) expression, and was accompanied by poly(ADP-ribose) polymerase (PARP) cleavage. Pretreatment with the antioxidant agent N-acetyl cysteine (NAC) not only reversed shikonin-induced ROS generation but also significantly attenuated the cytotoxic effects of shikonin in 143B cells. Furthermore, NAC attenuated shikonin-induced ERK phosphorylation. Taken together, our results reveal that shikonin increased ROS generation and ERK activation, and reduced Bcl2, which consequently caused the cells to undergo apoptosis. Therefore, shikonin may be a promising chemotherapeutic agent for osteosarcoma treatment.

Metastasis is the most common cause of cancer-related death in patients, and epithelial-to-mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation, and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biologic effects. In this study, we provided molecular evidence that is associated with the antimetastatic effect of berberine by showing a nearly complete inhibition on invasion (P , 0.001) of highly metastatic SiHa cells via reduced transcriptional activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Berberine reversed transforming growth factor-b1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific small interfering RNA also showed increased E-cadherin expression in SiHa cells. Berberine also reduced tumor-induced angiogenesis in vitro and in vivo. Importantly, an in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment of metastasis control.

Abstract. Lung cancer is among the most common causes of cancer-related mortality. It has a high mortality rate and resistance to chemotherapy due to its high metastatic potential. Naringenin, a bioactive compound identified in several fruits, displays anti-inflammatory and antitumor effects. Furthermore, naringenin mitigates the migration of several human cancer cell types. However, the effects of naringenin on lung cancer remain unclear. The current study investigated the mechanisms of naringenin on the migration of lung cancer A549 cells. The results indicate that significant alteration in A549 cell proliferation was observed in response to naringenin (0-300 µM) treatment for 24 and 48 h. Furthermore, a dose-dependent migration inhibition of A549 in the presence of naringenin was observed by healing and transwell migration assays. In addition, a zymography assay revealed that naringenin exhibited a concentration-dependent inhibition of matrix metalloproteinase (MMP)-2 and -9 activities. Furthermore, naringenin also inhibited the activities of AKT in a dose-dependent manner. These observations indicated that naringenin inhibited the migration of lung cancer A549 cells through several mechanisms, including the inhibition of AKT activities and reduction of MMP-2 and -9 activities.