The HSP90 inhibitor, NVP-AUY922, attenuates intrinsic PI3K inhibitor resistance in KRAS-mutant non-small cell lung cancer

Park, K.S.,Yang, H.,Choi, J.,Seo, S.,Kim, D.,Lee, C.H.,Jeon, H.,Kim, S.W.,Lee, D.H. Elsevier Science Ireland 2017 Cancer letters Vol.406 No.-

More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway. The HSP90 inhibitor AUY922 suppressed both PI3K/AKT/mTOR and RAF/MEK/ERK signaling, rendering cells sensitive to a PI3K inhibitor (omipalisib, GSK458). Combining these two drugs achieved a synergistic effect, even using only sub-therapeutic concentrations. Dual inhibition of the HSP90 and PI3K signaling pathways with sub-therapeutic doses of these combined anticancer drugs may represent a potent treatment strategy for KRAS-mutant NSCLC with intrinsic resistance to PI3K inhibition.

Down-regulation and aberrant cytoplasmic expression of GLTSCR2 in prostatic adenocarcinomas

Kim, J.Y.,Cho, Y.E.,Kim, G.Y.,Lee, H.L.,Lee, S.,Park, J.H. Elsevier Science Ireland 2013 Cancer letters Vol.340 No.1

GLTSCR2 is a nuclear/nucleolar protein that translocates to the nucleoplasm, suppressed and mutated in human cancers. Our aim in this study was to investigate whether downregulation or cytoplasmic expression of GLTSCR2 has any pathological significance in prostatic cancer development or progression. In this study we show that GLTSCR2 is suppressed in prostatic cancers and its expression is significantly associated with Gleason's scores. Furthermore, we investigated the pathogenetic mechanism of downregulation and cytoplasmic expression of GLTSCR2 in development or progression of prostatic cancers. Taken together, our results indicate that GLTSCR2 functions as a tumor suppressor in prostatic adenocarcinomas.

KRC-408, a novel c-Met inhibitor, suppresses cell proliferation and angiogenesis of gastric cancer

Hong, S.W.,Jung, K.H.,Park, B.H.,Zheng, H.M.,Lee, H.S.,Choi, M.J.,Yun, J.I.,Kang, N.S.,Lee, J.,Hong, S.S. Elsevier Science Ireland 2013 Cancer letters Vol.332 No.1

Among many cancer therapeutic targets, c-Met receptor tyrosine kinase has recently given particular attention. This kinase and its ligand, hepatocyte growth factor (HGF), play a central role in cell proliferation and the survival of several human cancers. Thus, we developed KRC-408 as a novel c-Met inhibitor and investigated its anti-cancer effects on human gastric cancer. KRC-408 inhibited the phosphorylation of c-Met and its constitutive downstream effectors such as phosphatidylinositol 3-kinase (PI3K), Akt, Mek, and Erk. This compound was found to exert anti-cancer effects stronger than those of 5-fluorouracil (5-FU) on gastric cancer cells, especially cell lines that overexpressed c-Met. Interestingly, cytotoxicity of KRC-408 was lower than that of 5-FU in normal gastric cells. Apoptosis induced by KRC-408 was accompanied by increased levels of cleaved caspase-3 and PARP as well as DNA condensation and fragmentation. Flow cytometry analysis showed an accumulation of gastric cancer cells in the G2/M phase with concomitant loss of cells in the S phase following treatment with this drug. In the angiogenesis studies, KRC-408 inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from rat aortic rings ex vivo along with blood vessel formation in a Matrigel plug assay in mice. Results of an in vivo mouse xenograft experiment showed that the administration of KRC-408 significantly delayed tumor growth in a dose-dependent manner, and suppressed Akt and Erk phosphorylation as well CD34 expression in tumor tissues. These findings indicate that KCR-408 may exert anti-tumor effects by directly affecting tumor cell growth or survival via the c-Met receptor tyrosine kinase pathway. We therefore suggest that KRC-408 is a novel therapeutic candidate effective against gastric cancers that overexpress c-Met.

Enhanced anti-cancer activity of human dendritic cells sensitized with gamma-irradiation-induced apoptotic colon cancer cells

Kim, S.K.,Yun, C.H.,Han, S.H. Elsevier Science Ireland 2013 Cancer letters Vol.335 No.2

Properly sensitized dendritic cells (DCs) can be an effective immunotherapeutic against cancers. We investigated the phenotypic and functional changes in human DCs sensitized with γ-irradiated colon cancer cell-line HT-29 (GIH). GIH induced maturation and activation of DCs. GIH-sensitized DCs showed increased cytotoxic activity against HT-29 through higher expression of perforin and granzyme B. They further induced expression of effector cytokines, cytotoxic molecules, and mucosal-homing receptor in autologous T-cells. Conclusively, these results suggest that effective anti-cancer activity is induced when DCs are sensitized with γ-irradiated cancer cells via both direct augmentation of the cytotoxicity and indirect activation of T cells.

Anti-cancer effect of HS-345, a new tropomyosin-related kinase A inhibitor, on human pancreatic cancer

Seo, J.H.,Jung, K.H.,Son, M.K.,Yan, H.H.,Ryu, Y.L.,Kim, J.,Lee, J.K.,Hong, S.,Hong, S.S. Elsevier Science Ireland 2013 Cancer letters Vol.338 No.2

Tropomyosin-related kinase A (TrkA) is emerging as an important player in carcinogenic progression. TrkA overexpression, which is associated with cell growth, proliferation, survival, and invasion, has been observed in pancreatic cancer. We therefore synthesized HS-345, a novel TrkA inhibitor, and evaluated its anti-cancer effect and underlying mechanism of action in pancreatic cancer. In this study, HS-345 effectively inhibited the growth and proliferation in three pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and BxPC-3). Activation of the TrkA/Akt signal cascade was also inhibited by HS-345 treatment in a dose-dependent manner. The pro-apoptotic effect of HS-345 was evidenced by increased levels of cleaved caspase-3 and cleaved PARP, and decrease of Bcl/Bax expression via mitochondria membrane potential, as well as elevated numbers of TUNEL-positive apoptotic cells. HS-345 was additionally found to exert anti-angiogenic effect by decreasing the expression of HIF-1α and VEGF, major factors of angiogenesis, which were also demonstrated by the suppression of tube formation and migration of VEGF-treated human umbilical vein endothelial cells along with inhibition of blood vessel formation by HS-345 in a Matrigel plug assay with mice. Results of our investigation show that HS-345 inhibited the TrkA/Akt signaling pathway resulting in cell growth/angiogenesis inhibition and apoptosis induction. Based on our data, we suggest that HS-345 is a potential candidate for treating pancreatic cancer.

Deleted in breast cancer 1 (DBC1) deficiency results in apoptosis of breast cancer cells through impaired responses to UV-induced DNA damage

Kim, W.,Kim, J.E. Elsevier Science Ireland 2013 Cancer letters Vol.333 No.2

DBC1 (deleted in breast cancer 1) participates in the regulation of cell survival and death in response to various stimuli. In particular, DBC1 promotes cell death upon DNA damage through inhibition of SIRT1 deacetylase. However, the SIRT1-independent functions of DBC1 in the regulation of DNA damage response are less well understood. Therefore, we analyzed the DNA damage response in Hs578T breast cancer cell line in which the DBC1-SIRT1 interaction is barely detectable. DBC1-siRNA transfected cells showed a failure in the DNA damage checkpoint and the accumulation of genomic damage following UV irradiation. In addition, DBC1-deficient cells exhibited less JNK activation. Finally, the interruptions of signaling in DBC1-depleted cells contributed to cell death in response to UV irradiation. Overall, these data suggest that DBC1 is essential for a fully efficient and effective response to UV irradiation. Therefore, DBC1 plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress.

Polyphenol tri-vanillic ester 13c inhibits P-JAK2V617F and Bcr-Abl oncokinase expression in correlation with STAT3/STAT5 inactivation and apoptosis induction in human leukemia cells

Trecul, A.,Morceau, F.,Gaigneaux, A.,Orsini, M.,Chateauvieux, S.,Grandjenette, C.,Dicato, M.,Diederich, M. Elsevier Science Ireland 2013 Cancer letters Vol.340 No.1

Constitutive activity of kinases has been reported in many types of cancers, so that inhibition of ''onco-kinases'' became a validated anti-cancer strategy. We found that the polyphenol 13c, a tri-vanillate derivative, inhibited kinase phosphorylation in leukemia cells. P-JAK2, P-Src and P-PI3Kp85 inhibition occurred independently of phosphatase involvement in JAK2V617F expressing HEL cells while 13c inhibited Bcr-Abl expression without inhibition of phosphorylation in chronic myelogenous leukemia cell lines (K562, MEG-01). In correlation with kinase inhibition, 13c abolished constitutive P-STAT3/P-STAT5 expression, down-regulated Mcl-1 and c-Myc gene expression and induced apoptosis. Altogether, polyphenol 13c displays potential antitumor activities by affecting onco-kinases and STAT activities.

MiR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer

Noh, J.H.,Chang, Y.G.,Kim, M.G.,Jung, K.H.,Kim, J.K.,Bae, H.J.,Eun, J.W.,Shen, Q.,Kim, S.J.,Kwon, S.H.,Park, W.S.,Lee, J.Y.,Nam, S.W. Elsevier Science Ireland 2013 Cancer letters Vol.335 No.2

Aberrant regulation of histone deacetylase 2 (HDAC2) plays a pivotal role in the development of hepatocellular carcinoma (HCC), but, the underlying mechanism leading to HDAC2 overexpression is not well understood. We performed microRNA (miRNA) profiling analysis in a subset of HCCs, and identified four down-regulated miRNAs that may target HDAC2 in HCC. Ectopic expression of miRNA mimics evidenced that miR-145 suppresses HDAC2 expression in HCC cells. This treatment repressed cancer cell growth and recapitulated HDAC2 knockdown effects on HCC cells. In conclusion, we suggest that loss or suppression of miR-145 may cause aberrant overexpression of HDAC2 and promote HCC tumorigenesis.

CBX8 suppresses Sirtinol-induced premature senescence in human breast cancer cells via cooperation with SIRT1

Lee, S.H.,Um, S.J.,Kim, E.J. Elsevier Science Ireland 2013 Cancer letters Vol.335 No.2

Stress-induced premature senescence (SIPS) has been implicated in the suppression of carcinogenesis. We identified chromodomain protein 8 (CBX8), a Polycomb group (PcG) protein, as a novel binding partner of SIRT1. The interaction between CBX8 and SIRT1 was demonstrated by immunoprecipitation, GST pull-down, fluorescence microscopy, and cooperation for transcriptional repression. Like SIRT1, CBX8 repressed premature senescence and growth arrest induced by the SIRT1 inhibitor Sirtinol in MCF7 cells, which was reversed by depleting CBX8. CBX8 cooperated with SIRT1 for suppressing p53 acetylation induced by Sirtinol and etoposide/TSA. Upon ectopic expression, CBX8 or SIRT1 repressed the expression of p21<SUP>WAF1</SUP> by inhibiting p53 binding to the promoter. We provide the first evidence that CBX8 plays a potential role in regulating premature senescence in human breast cancer cells through cooperation with SIRT1.

Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer

Shrimali, D.,Shanmugam, M.K.,Kumar, A.P.,Zhang, J.,Tan, B.K.H.,Ahn, K.S.,Sethi, G. Elsevier Science Ireland 2013 Cancer letters Vol.341 No.2

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a natural occurring anthraquinone derivative isolated from roots and barks of numerous plants, molds, and lichens. It is found as an active ingredient in different Chinese herbs including Rheum palmatum and Polygonam multiflorum, and has diuretic, vasorelaxant, anti-bacterial, anti-viral, anti-ulcerogenic, anti-inflammatory, and anti-cancer effects. The anti-inflammatory effects of emodin have been exhibited in various in vitro as well as in vivo models of inflammation including pancreatitis, arthritis, asthma, atherosclerosis and glomerulonephritis. As an anti-cancer agent, emodin has been shown to suppress the growth of various tumor cell lines including hepatocellular carcinoma, pancreatic, breast, colorectal, leukemia, and lung cancers. Emodin is a pleiotropic molecule capable of interacting with several major molecular targets including NF-κB, casein kinase II, HER2/neu, HIF-1α, AKT/mTOR, STAT3, CXCR4, topoisomerase II, p53, p21, and androgen receptors which are involved in inflammation and cancer. This review summarizes reported anti-inflammatory and anti-cancer effects of emodin, and re-emphasizes its potential therapeutic role in the treatment of inflammatory diseases and cancer.