Anti­chondrocyte apoptosis effect of genistein in treating inflammation­induced osteoarthritis.

Osteoarthritis (OA) is a chronic disease that is mainly characterized by chondrocyte degeneration. Inflammatory mediators participate in the development of OA, leading to chondrocyte apoptosis and destruction of the cartilage. Genistein is the major active component of isoflavone, with a chemical composition and a biological effect that is similar to that of estrogens, which prevents the degradation of cartilage; however, its underlying mechanisms of action remain unknown. The aim of the present study was to investigate the anti­apoptotic effects of genistein on chondrocytes for the treatment of inflammation­induced OA. Interleukin (IL)­1ß was used to establish a chondrocyte OA model. After treatment with different concentrations of genistein, western blotting identified that expression levels of collagen II and aggrecan were increased in a concentration­dependent manner, while caspase 3 expression gradually decreased after genistein application. Moreover, flow cytometry and ELISA results demonstrated that genistein could decrease chondrocyte apoptosis and reduce the levels of tumor necrosis factor (TNF)­α in a dose­dependent manner. Furthermore, the in vitro data were evaluated in an OA rat model. Genistein increased the collagen and acid glycosaminoglycan content, as well as decreased the levels of TNF­α and IL­1ß. Genistein also promoted the expression levels of collagen II and aggrecan in the articular cartilage, and decreased the expression of caspase 3, thus alleviating cartilage degradation. In conclusion, the results indicated that genistein mediated inflammation and had an anti­apoptotic role in treating OA. Therefore, genistein may serve as an alternative treatment for OA.

MALAT1: A long non-coding RNA highly associated with human cancers.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a well-known lncRNA associated with numerous diseases, particularly cancer, has received increased attention. The expression of MALAT1 was determined to be upregulated in numerous types of tumors and MALAT1 exhibited effects on tumor cell proliferation, migration, invasion and apoptosis. The abnormal expression of MALAT1 was identified in almost in every organ of the digestive system. MALAT1 performed an important role in the pathological alterations of organs that are associated with sex hormones and several reproductive system cancers. MALAT1 participates in molecular pathways. In the clinical application of MALAT1, MALAT1 was considered as a potential biomarker for the diagnosis and prediction of cancers, and may also serve as therapeutic target for treatment of specific tumors. This review summarizes the abnormal expression of MALAT1 in cancer, its significant effect on the primary features of cancer, as well as the underlying molecular mechanisms of MALAT1 in various cancers. According to studies on MALAT1, we introduce the upstream and downstream substances associated with the function of MALAT1. These reviewed studies promote the clinical application of MALAT1 in the aspect of diagnosis and treatment of different cancers, and may help point out new study directions for MALAT1.

Downregulation of MiR-1297 predicts poor prognosis and enhances gastric cancer cell growth by targeting CREB1.

Dysregulation of mircoRNAs (miRs) that act as tumor suppressors or oncogenes is participated in tumorigenesis and progression. The aim of the study is to investigate the role and mechanism of miR-1297 in gastric cancer (GC). Here, we demonstrated that miR-1297 expression was significantly lower in GC tissue samples compared to adjacent normal tissue samples in 62 cases GC patients. Lower miR-1297 expression positively associated with larger tumor size, lymph node metastasis, advanced TNM stage and poor survival time of patients. Upregulation of miR-1297 significantly inhibited cell proliferation and cell colony forming abilities in vitro. However, downregulation of miR-1297 can cause the reverse biological function changes. In vivo, miR-1297 overexpression suppressed tumor growth. Luciferase reporter assay showed that CREB1 was a direct target of miR-1297 in GC. MiR-1297 inhibited the expression of CREB1 by targeting the 3'UTR of CREB1. Additionally, we demonstrated that CREB1 overexpression rescued the effects on GC cell growth induced by miR-1297. Therefore, these results indicated that miR-1297 might be a prognostic predictor for GC and potential target of GC treatment.

Salvianolic acid B reverses multidrug resistance in nude mice bearing human colon cancer stem cells.

Salvianolic acid B (SalB) is a water­soluble phenolic compound, extractable from Salvia miltiorrhiza, and has previously been demonstrated to reverse tumor multidrug resistance (MDR) in colon cancer cells. Cancer stem cells (CSCs) are closely associated with drug resistance. Therefore, establishing a nude mouse model bearing human colon CSCs is important for the study of the mechanisms underlying colon cancer drug resistance as well as the reversal of drug resistance. The present study aimed to establish a nude mouse model bearing human colon CSCs and to investigate the effects of SalB on the drug resistance exhibited by the nude mouse model as well as determine its underlying mechanism. Cells from two colon cancer cell lines (LoVo and HCT­116) were cultured in serum­free medium to obtain CSCs­enriched spheroid cells. Following this, nude mice were transplanted with LoVo and HCT­116 colon CSCs to establish the CSC nude mouse model, which was subsequently demonstrated to exhibit MDR. The results of the present study revealed that following treatment with SalB, the chemotherapeutic drug resistance of xenografts was reversed to a certain extent. Western blot analysis was performed to investigate the expression levels of cluster of differentiation (CD)44, CD133, transcription factor sox­2 (SOX2) and ATP­binding cassette sub­family G member 2 (ABCG2) proteins, and the results demonstrated that treatment with SalB downregulated the expression of CD44, SOX2 and ABCG2 proteins in both LoVo and HCT­116 colon CSCs xenografts. In conclusion, the results of the present study revealed that a serum­free suspension method can be performed to successfully isolate colon CSCs. In addition, a nude mice bearing colon CSCs animal model was successfully established, and associated tumors were confirmed to exhibit MDR. Furthermore, SalB was demonstrated to successfully reverse MDR in nude mice bearing LoVo and HCT­116 colon CSCs, as well as suppress the expression of CD44, SOX2 and ABCG2 proteins.

Zhi Zhen Fang formula reverses Hedgehog pathway mediated multidrug resistance in colorectal cancer.

Zhi-Zhen-Fang (ZZR), a Traditional Chinese Medicine (TCM) formula, has been clinically used in China to treat drug-resistant colorectal cancer (CRC) patients as an adjuvant. In this study, the efficacy of ZZR in suppressing multidrug resistance (MDR) on CRC was evaluated in vitro and in vivo. We observed that ZZR enhanced the sensitivity of chemotherapeutic drugs and induced apoptosis in a dose- and time-dependent mannner in CRC MDR cells. Interestingly, signaling of Hedgehog pathway, particularly Gli1, was also inhibited by ZZR. This effect of ZZR in reversing drug resistance and suppressing Gli1 was attenuated by a Hedgehog activator (SAG). Furthermore, ZZR inhibited MDR CRC tumor growth in a xenograft mouse model as well as downregulated Gli1 levels. This study provided the first direct evidence demonstrating ZZR can attenuate MDR by repressing Hedgehog signaling in human CRC.

Salvianolic acid B reverses multidrug resistance in HCT­8/VCR human colorectal cancer cells by increasing ROS levels.

Salvianolic acid B (SalB) a water­soluble phenolic compound, extracted from Salvia miltiorrhiza, has previously been demonstrated to reverse tumor multidrug resistance (MDR), including in colorectal cancer. Reactive oxygen species (ROS) are oxygen radicals generated during aerobic metabolism (superoxide and hydroxyl radicals) and superoxide easily generating free radicals (H2O2). The concept that increased ROS levels can lead to augmented tumor cell­sensitivity to chemotherapy drugs has become notable. The aim of the present study was to elucidate the role of ROS in mediating the effect of SalB on drug resistance and the correlation with drug resistance­associated protein, P­glycoprotein (P­gp), and apoptosis­associated proteins, B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X (Bax). In the current study, through utilizing the multidrug resistant colorectal cancer cell line, HCT­8/VCR, it was demonstrate that SalB reversed MDR in HCT­8/VCR. In addition, SalB significantly increased ROS levels, which may have accelerated the apoptosis of HCT­8/VCR cells by downregulating Bcl­2 and increasing Bax protein expression. Furthermore the increased intracellular ROS levels may have inhibited P­gp expression at the gene and protein levels. In conclusion, the data of the current study demonstrate that SalB reversed MDR in HCT­8/VCR cells, and the effect is associated with increased ROS levels, which may downregulate P­gp expression and promote tumor cell apoptosis, which in turn increases the sensitivity of drug­resistant cells to chemotherapy drugs.

Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1α in vitro.

Hypoxia in tumors is closely related to drug resistance. It has not been verified whether hypoxia-inducible factor-1α (HIF-1α) or ABCG2 is related to hypoxia-induced resistance. Ursolic acid (UA), when used in combination with cisplatin can significantly increase the sensitivity of ovarian cancer stem cells (CSCs) to cisplatin, but the exact mechanism is unknown. The cell growth inhibitory rate of cisplatin under different conditions was evaluated using Cell Counting Kit-8 (CCK-8) in adherence and sphere cells (SKOV3, A2780, and HEY). The expression of HIF-1α and ABCG2 was tested using quantitative PCR, western blotting, and immuno-fluorescence under different culture conditions and treated with UA. Knockdown of HIF-1α by shRNA and LY294002 was used to inhibit the activity of PI3K/Akt pathway. Ovarian CSCs express stemness-related genes and drug resistance significantly higher than normal adherent cells. Under hypoxic conditions, the ovarian CSCs grew faster and were more drug resistant than under normoxia. UA could inhibit proliferation and reverse the drug resistance of ovarian CSC by suppressing ABCG2 and HIF-1α under different culture conditions. HIF-1α inhibitor YC-1 combined with UA suppressed the stemness genes and ABCG2 under hypoxic condition. The PI3K/Akt signaling pathway activation plays an important functional role in UA-induced downregulation of HIF-1α and reduction of ABCG2. UA inhibits the proliferation and reversal of drug resistance in ovarian CSCs by suppressing the expression of downregulation of HIF-1α and ABCG2.