Po-Cheng Lin

MicroRNA in lung cancer

MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as endogenous negative gene regulators. Dysfunctions of miRNAs are frequently found in malignancies, including lung cancer. In this review, we summarise the current understanding of miRNAs in lung cancer tumourigenesis, and highlight their potential in overcoming drug resistance, abetting histological sub-classification techniques, and serving as biomarkers for lung cancer risk stratification and outcome prediction.

Extended O6-methylguanine methyltransferase promoter hypermethylation following n-butylidenephthalide combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on inhibition of human hepatocellular carcinoma cell growth.

Epigenetic alteration of DNA methylation plays an important role in the regulation of gene expression associated with chemosensitivity of human hepatocellular (HCC) carcinoma cells. With the aim of improving the chemotherapeutic efficacy for HCC, the effect of the naturally occurring compound n-butylidenephthalide (BP), which is isolated from a chloroform extract of Angelica sinensis, was investigated. In both HepG2 and J5 HCC cell lines, a synergistic antiproliferative effect was observed when a low dosage of BP was combined with the chemotherapeutic drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU is an alkylating agent, and it prompts us to examine one of DNA repair genes, O(6)-methylguanine methyltransferase (MGMT). It was evident from methylation-specific polymerase chain reaction (PCR) analysis that BP/BCNU combined treatment caused a time- and concentration-dependent enhancement of MGMT promoter methylation. Overexpression of MGMT could abolish BP-induced growth inhibition in the J5 tumor cell line as measured by colony formation assay. When BP was combined with BCNU and administered, it showed significant antitumor effects in both HepG2 and J5 xenograft tumors as compared with the use of only one of these drugs. The BCNU-induced apoptosis and inhibited MGMT protein expression in HCC cells, both in vitro and in vivo, resulting from the combination treatment of BP and BCNU suggest a potential clinical use of this compound for improving the prognosis for HCCs.

Overexpression of the orphan receptor Nur77 and its translocation induced by PCH4 may inhibit malignant glioma cell growth and induce cell apoptosis.

In previous study, n‐butylidenephthalide (BP), a natural compound from Angelica sinensis, has anti‐glioblastoma multiform (GBM) cell effects. In this study, we modified BP structure to increase anti‐GBM cell effects. The anti‐GBM cell effects of one derivative of BP, (Z)‐N‐(2‐(dimethylamino)ethyl)‐2‐(3‐((3‐oxoisobenzofuran‐1(3H)‐ylidene)methyl)phenoxy)acetamide (PCH4) were tested in vitro and in vivo.

The antisenescence effect of Trans-cinnamaldehyde on adipose-derived stem cells

As assuring cell quality is an essential parameter for the success of stem cell therapy, the impact of various senescence-inducing stress signals, and strategies to circumvent them, has been an important area of focus in stem cell research. The aim of this study was to demonstrate the capacity of trans-cinnamaldehyde (TC) in reversing stress-induced senescence and maintaining the quality of stem cells in a chemically (H2O2)-induced cell senescence model. Because of the availability and the promising application potential in regenerative medicine, adipose-derived stem cells (ADSCs) were chosen for the study. We found that H2O2 treatment resulted in the expression of senescence characteristics in the ADSCs, including decreased proliferation rate, increased senescence-associated β-galactosidase (SA-β-gal) activity, decreased silent mating type information regulation 2 homolog (SIRT1) expression, and decreased telomerase activity. However, TC treatment was sufficient to rescue or reduce the effects of H2O2 induction, ultimately leading to an increased proliferation rate, a decrease in the percentage of SA-β-gal-positive cells, upregulation of SIRT1 expression, and increased telomerase activity of the senescent ADSCs at the cellular level. Moreover, a chemically induced liver fibrosis animal model was used to evaluate the functionality of these rescued cells in vivo. Liver dysfunction was established by injecting 200 mg/kg thioacetamide (TAA) intraperitoneally into Wistar rats every third day for 60 days. The experimental rats were separated into groups: normal group (rats without TAA induction), sham group (without ADSC transplantation), positive control group (transplanted with normal ADSCs), H2O2 group (transplanted with H2O2-induced senescent ADSCs), and H2O2 + TC group (transplanted with ADSCs pretreated with H2O2 and then further treated with TC). In the transplantation group, 1 × 106 human ADSCs were introduced into each rat via direct liver injection. Based on the biochemical analysis and immunohistochemical staining results, it was determined that the therapeutic effects on liver fibrosis by the induced senescent ADSCs (H2O2 group) were not as significant as those exerted by the normal ADSCs (the positive control group). However, the H2O2 + TC group showed significant reversal of liver damage when compared to the H2O2 group 1 week posttransplantation. These data confirmed that the TC treatment had the potential to reduce the effects of H2O2-induced senescence and to restore in vivo functionality of the induced senescent ADSCs. It is therefore suggested that TC has potential applications in maintaining the quality of stem cells and could aid in treating senescence-related disorders.

Abstract 770: The orphan receptor Nur77 overexpression and translocation induced by PCH4 may inhibit malignant brain tumor growth and induce cell apoptosis

N-butylidenephthalide(BP), a nature compound from Angelica sinensis, has the antitumor effect in vitro and in vivo. Further, we modified the chemical structure of BP for increasing the antitumor effect and one derivative is (Z)-N-(2-(dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide, PCH4, has 4 times tumor inhibition on human glioblastoma multiform DBTRG-05MG cells. The IC50 of PCH4 on DBTRG-05MG cells is 50 μg/ml. The PCH4 induced apoptosis was related to Nur77 expression and translocation from nucleus to cytosol. Furthermore, the inhibition of PCH4-induced Nur77 expression by Nur77 siRNA can reduce the PCH4-induced apoptosis. In addition, The PCH4-induced apoptosis was associated with JNK pathway. The JNK inhibitor, SP600125, inhibited the Nur77 mRNA expression and reduced the PCH4-induced apoptosis. In conclusion, It suggesting us that the PCH4, the derivatives of BP, induce the Nur77-mediated apoptosis through the JNK pathway and this mechanism different from BP may increase the antitumor effect on GBM cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 770.