Man Gang Lee

Bio: Man Gang Lee is an academic researcher from National Sun Yat-sen University. The author has contributed to research in topics: Apoptosis & Downregulation and upregulation. The author has an hindex of 3, co-authored 3 publications receiving 56 citations. Previous affiliations of Man Gang Lee include Yahoo!.

Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90.

Abstract: Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1–68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9–99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent.

Isoaaptamine Induces T-47D Cells Apoptosis and Autophagy via Oxidative Stress

Abstract: Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was evaluated revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. In a concentration-dependent manner, isoaaptamine inhibited the growth of T-47D cells as indicated by short-(MTT) and long-term (colony formation) anti-proliferative assays. The cytotoxic effect of isoaaptamine was mediated through apoptosis as indicated by DNA ladder formation, caspase-7 activation, XIAP inhibition and PARP cleavage. Transmission electron microscopy and flow cytometric analysis using acridine orange dye indicated that isoaaptamine treatment could induce T-47D cells autophagy. Immunoblot assays demonstrated that isoaaptamine treatment significantly activated autophagy marker proteins such as type II LC-3. In addition, isoaaptamine treatment enhanced the activation of DNA damage (γH2AX) and ER stress-related proteins (IRE1 α and BiP). Moreover, the use of isoaaptamine resulted in a significant increase in the generation of reactive oxygen species (ROS) as well as in the disruption of mitochondrial membrane potential (MMP). The pretreatment of T-47D cells with an ROS scavenger, N-acetyl-l-cysteine (NAC), attenuated the apoptosis and MMP disruption induced by isoaaptamine up to 90%, and these effects were mediated by the disruption of nuclear factor erythroid 2-related factor 2 (Nrf 2)/p62 pathway. Taken together, these findings suggested that the cytotoxic effect of isoaaptamine is associated with the induction of apoptosis and autophagy through oxidative stress. Our data indicated that isoaaptamine represents an interesting drug lead in the war against breast cancer.

Tackling the Cytotoxic Effect of a Marine Polycyclic Quinone-Type Metabolite: Halenaquinone Induces Molt 4 Cells Apoptosis via Oxidative Stress Combined with the Inhibition of HDAC and Topoisomerase Activities

Abstract: A marine polycyclic quinone-type metabolite, halenaquinone (HQ), was found to inhibit the proliferation of Molt 4, K562, MDA-MB-231 and DLD-1 cancer cell lines, with IC50 of 0.48, 0.18, 8.0 and 6.76 μg/mL, respectively. It exhibited the most potent activity against leukemia Molt 4 cells. Accumulating evidence showed that HQ may act as a potent protein kinase inhibitor in cancer therapy. To fully understand the mechanism of HQ, we further explored the precise molecular targets in leukemia Molt 4 cells. We found that the use of HQ increased apoptosis by 26.23%–70.27% and caused disruption of mitochondrial membrane potential (MMP) by 17.15%–53.25% in a dose-dependent manner, as demonstrated by Annexin-V/PI and JC-1 staining assays, respectively. Moreover, our findings indicated that the pretreatment of Molt 4 cells with N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger, diminished MMP disruption and apoptosis induced by HQ, suggesting that ROS overproduction plays a crucial rule in the cytotoxic activity of HQ. The results of a cell-free system assay indicated that HQ could act as an HDAC and topoisomerase catalytic inhibitor through the inhibition of pan-HDAC and topoisomerase IIα expression, respectively. On the protein level, the expression of the anti-apoptotic proteins p-Akt, NFκB, HDAC and Bcl-2, as well as hexokinase II was inhibited by the use of HQ. On the other hand, the expression of the pro-apoptotic protein Bax, PARP cleavage, caspase activation and cytochrome c release were increased after HQ treatment. Taken together, our results suggested that the antileukemic effect of HQ is ROS-mediated mitochondrial apoptosis combined with the inhibitory effect on HDAC and topoisomerase activities.

DLK2 Acts as a Potential Prognostic Biomarker for Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis

Abstract: Clear cell renal cell carcinoma (ccRCC) is the most common RCC subtype with a high mortality. It has been reported that delta-like 1 homologue (DLK1) participates in the tumor microenvironmental remodeling of ccRCC, but the relationship between delta-like 2 homologue (DLK2, a DLK1 homologue) and ccRCC is still unclear. Thus, this study aims to investigate the role of DLK2 in the biological function and disease prognosis of ccRCC using bioinformatics analysis. The TNMplot database showed that DLK2 was upregulated in ccRCC tissues. From the UALCAN analysis, the overexpression of DLK2 was associated with advanced stage and high grade in ccRCC. Moreover, the Kaplan-Meier plotter (KM Plotter) database showed that DLK2 upregulation was associated with poor survival outcome in ccRCC. By the LinkedOmics analysis, DLK2 signaling may participated in the modulation of ccRCC extracellular matrix (ECM), cell metabolism, ribosome biogenesis, TGF-β signaling and Notch pathway. Besides, Tumor Immune Estimation Resource (TIMER) analysis showed that the macrophage and CD8+ T cell infiltrations were associated with good prognosis in ccRCC patients. Finally, DLK2 overexpression was associated with the reduced macrophage recruitments and the M1–M2 polarization of macrophage in ccRCC tissues. Together, DLK2 may acts as a novel biomarker, even therapeutic target in ccRCC. However, this study lacks experimental validation, and further studies are required to support this viewpoint.

Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets.

Abstract: Human DNA topoisomerase II is an important target in anticancer therapy. Despite the clinical success of drugs that target topoisomerase II, the development of resistant cancer cells can limit their clinical efficacy. To maximize the therapeutic potential of anticancer drugs, combination therapies and multitarget drugs have been suggested in many studies, where the use of multitarget drugs is advantageous from a pharmacokinetic point of view. There are various different options for the preparation of dual-target or multiple-target inhibitors, as topoisomerase II is both structurally (e.g., topoisomerase I, Hsp90, and kinases) and functionally (e.g., histone deacetylases and proteasome) connected to many validated anticancer targets. In this Perspective, we discuss the scientific background behind targeting topoisomerase II together with a number of other targets important in cancer therapy, review the present status, and discuss further options in the field.

A Marine Terpenoid, Heteronemin, Induces Both the Apoptosis and Ferroptosis of Hepatocellular Carcinoma Cells and Involves the ROS and MAPK Pathways

Abstract: Hepatocellular carcinoma (HCC) is a leading cause of death, resulting in over 700 thousand deaths annually worldwide. Chemotherapy is the primary therapeutic strategy for patients with late-stage HCC. Heteronemin is a marine natural product isolated from Hippospongia sp. that has been found to protect against carcinogenesis in cholangiocarcinoma, prostate cancer, and acute myeloid leukemia. In this study, heteronemin was found to inhibit the proliferation of the HCC cell lines HA22T and HA59T and induce apoptosis via the caspase pathway. Heteronemin treatment also induced the formation of reactive oxygen species (ROS), which are associated with heteronemin-induced cell death, and to trigger ROS removal by mitochondrial SOD2 rather than cytosolic SOD1. The mitogen-activated protein kinase (MAPK) signaling pathway was associated with ROS-induced cell death, and heteronemin downregulated the expression of ERK, a MAPK that is associated with cell proliferation. Inhibitors of JNK and p38, which are MAPKs associated with apoptosis, restored heteronemin-induced cell death. In addition, heteronemin treatment reduced the expression of GPX4, a protein that inhibits ferroptosis, which is a novel form of nonapoptotic programmed cell death. Ferroptosis inhibitor treatment also restored heteronemin-induced cell death. Thus, with appropriate structural modification, heteronemin can act as a potent therapeutic against HCC.

δ-Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells.

Abstract: Objectives Prostate cancer, after the phase of androgen dependence, may progress to the castration-resistant prostate cancer (CRPC) stage, with resistance to standard therapies. Vitamin E-derived tocotrienols (TTs) possess a significant antitumour activity. Here, we evaluated the anti-cancer properties of δ-TT in CRPC cells (PC3 and DU145) and the related mechanisms of action. Materials and methods MTT, Trypan blue and colony formation assays were used to assess cell viability/cell death/cytotoxicity. Western blot, immunofluorescence and MTT analyses were utilized to investigate apoptosis, ER stress and autophagy. Morphological changes were investigated by light and transmission electron microscopy. Results We demonstrated that δ-TT exerts a cytotoxic/proapoptotic activity in CRPC cells. We found that in PC3 cells: (a) δ-TT triggers both the endoplasmic reticulum (ER) stress and autophagy pathways; (b) autophagy induction is related to the ER stress, and this ER stress/autophagy axis is involved in the antitumour activity of δ-TT; in autophagy-defective DU145 cells, only the ER stress pathway is involved in the proapoptotic effects of δ-TT; (c) in both CRPC cell lines, δ-TT also induces an intense vacuolation prevented by the ER stress inhibitor salubrinal and the protein synthesis inhibitor cycloheximide, together with increased levels of phosphorylated JNK and p38, supporting the induction of paraptosis by δ-TT. Conclusions These data demonstrate that apoptosis, involving ER stress and autophagy (in autophagy positive PC3 cells), and paraptosis are involved in the anti-cancer activity of δ-TT in CRPC cells.

New Drugs from the Sea: Pro-Apoptotic Activity of Sponges and Algae Derived Compounds.

Abstract: Natural compounds derived from marine organisms exhibit a wide variety of biological activities. Over the last decades, a great interest has been focused on the anti-tumour role of sponges and algae that constitute the major source of these bioactive metabolites. A substantial number of chemically different structures from different species have demonstrated inhibition of tumour growth and progression by inducing apoptosis in several types of human cancer. The molecular mechanisms by which marine natural products activate apoptosis mainly include (1) a dysregulation of the mitochondrial pathway; (2) the activation of caspases; and/or (3) increase of death signals through transmembrane death receptors. This great variety of mechanisms of action may help to overcome the multitude of resistances exhibited by different tumour specimens. Therefore, products from marine organisms and their synthetic derivates might represent promising sources for new anticancer drugs, both as single agents or as co-adjuvants with other chemotherapeutics. This review will focus on some selected bioactive molecules from sponges and algae with pro-apoptotic potential in tumour cells.

Role of Natural Products in Modulating Histone Deacetylases in Cancer.

Abstract: Histone deacetylases (HDACs) are enzymes that can control transcription by modifying chromatin conformation, molecular interactions between the DNA and the proteins as well as the histone tail, through the catalysis of the acetyl functional sites removal of proteins from the lysine residues. Also, HDACs have been implicated in the post transcriptional process through the regulation of the proteins acetylation, and it has been found that HDAC inhibitors (HDACi) constitute a promising class of pharmacological drugs to treat various chronic diseases, including cancer. Indeed, it has been demonstrated that in several cancers, elevated HDAC enzyme activities may be associated with aberrant proliferation, survival and metastasis. Hence, the discovery and development of novel HDACi from natural products, which are known to affect the activation of various oncogenic molecules, has attracted significant attention over the last decade. This review will briefly emphasize the potential of natural products in modifying HDAC activity and thereby attenuating initiation, progression and promotion of tumors.