CD-200 induces apoptosis and inhibits Bcr-Abl signaling in imatinib-resistant chronic myeloid leukemia with T315I mutation

FANG, ZHENGHUAN,JUNG, KYUNG HEE,YAN, HONG HUA,KIM, SOO JUNG,SON, MI KWON,RUMMAN, MARUFA,LEE, HYUNSEUNG,KIM, KI WOON,YOO, HYE-DONG,HONG, SOON-SUN Spandidos Publications 2015 International journal of oncology Vol.47 No.1

<P>Chronic myeloid leukemia (CML) is characterized by a constitutively active Bcr-Abl tyrosine kinase. Although Imatinib has been proven to be an effective drug against CML, its resistance has been observed with disease relapse due to T315I predominant point mutation. Liriodendron tulipifera L., one of the fastest growing hardwood tree species, exerts antioxidant activity and anti-inflammatory effects. However, its anticancer effect has been minimally reported. In this study, we extracted CD-200 from Liriodendron tulipifera L. and investigated its effect on cell survival or apoptosis in CML cells with Bcr-Abl/T315I (BaF3/T315I) as well as wild-type Bcr-Abl (BaF3/WT). CD-200 inhibited cell proliferation in the BaF3/WT cells, and also in the BaF3/T315I cells with Imatinib resistance. Moreover, it strongly inhibited Bcr-Abl signaling pathways in a dose-dependent manner. Also, it significantly increased the sub-G1 phase and the expression of cleaved PARP and caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we observed that CD-200 induced apoptosis with a loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin. Furthermore, CD-200 showed a significant inhibition in tumor growth, compared to Imatinib in BaF3/T315I mouse xenograft models. Taken together, our study demonstrates that CD-200 exhibits apoptosis induction and anti-proliferative effect by blocking the Bcr-Abl signaling pathways in the Bcr-Abl/T315I with resistance to Imatinib. We suggest that CD-200 may be a natural product to target Bcr-Abl and overcome Imatinib resistance in CML patients.</P>

A novel tropomyosin-related kinase A inhibitor, KK5101 to treat pancreatic cancer

Fang, Zhenghuan,Han, Boreum,Jung, Kyung Hee,Lee, Ju-Hyeon,El-Damasy, Ashraf Kareem,Gadhe, Changdev G.,Kim, Soo Jung,Yan, Hong Hua,Park, Jung Hee,Lee, Ji Eun,Kang, Yeo Wool,Pae, Ae Nim,Keum, Gyochang,H Elsevier 2018 Cancer letters Vol.426 No.-

<P><B>Abstract</B></P> <P>Tropomyosin-related kinase A (TrkA) plays important roles in tumor cell growth and survival signaling and contributes to chemo-resistance in pancreatic cancer. Therefore, we developed KK5101, a novel TrkA target inhibitor and assessed its anti-cancer effects and investigated underlying mechanism of action in pancreatic cancer. KK5101 was characterized to inhibit TrkA selectively and potently by protein binding assay. It effectively inhibited the growth and proliferation of pancreatic cancer cells. Also, KK5101 increased apoptosis with loss of mitochondrial membrane potential, as evidenced by increases of cytochrome <I>c</I> releases. It increased numbers of TUNEL-positive apoptotic cells, and cell death including early and late apoptosis by Annexin V assay. In addition, activation of the TrkA signaling cascades including p-AKT, p-MEK, and p-STAT3 were inhibited by KK5101 treatment <I>in vitro</I>, as well as <I>ex vivo</I> tumor spheroid models, resulting in potent induction of apoptosis. Importantly, KK5101 also significantly attenuated tumor growth of <I>in vivo</I> pancreatic cancer models. These findings indicate that KK5101 may exert antitumor effects by directly affecting cancer cell growth or survival via inhibition of TrkA signaling pathway. We therefore suggest that KK5101 is a novel therapeutic candidate for treating pancreatic cancer.</P> <P><B>Highlights</B></P> <P> <UL> <LI> KK5101 specifically binds in an allosteric pocket of TrkA. </LI> <LI> KK5101 effectively inhibits survival/proliferation and induced apoptosis in pancreatic cancer. </LI> <LI> KK5101 may be a highly selective inhibitor for TrkA, inhibiting the PI3K/AKT, Raf/MAPK, and STAT3 signaling pathways. </LI> </UL> </P>

Melatonin Synergizes with Sorafenib to Suppress Pancreatic Cancer via Melatonin Receptor and PDGFR-β/STAT3 Pathway

Fang, Zhenghuan,Jung, Kyung Hee,Yan, Hong Hua,Kim, Soo-Jung,Rumman, Marufa,Park, Jung Hee,Han, Boreum,Lee, Ji Eun,Kang, Yeo wool,Lim, Joo Han,Hong, Soon Sun S. Karger AG 2018 CELLULAR PHYSIOLOGY AND BIOCHEMISTRY Vol.47 No.5

<P><B><I>Background/Aims:</I></B> Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors with poor prognosis. Conventional chemotherapies including gemcitabine have failed owing to weak response and side effects. Hence novel treatment regimens are urgently needed to improve the therapeutic efficacy. In this study, we aimed to assess the anticancer activity of melatonin and sorafenib as a novel therapy against PDAC. <B><I>Methods:</I></B> We used various apoptosis assay and PDAC xenograft model to assess anticancer effect <I>in vitro</I> and <I>in vivo</I>. We applied phospho-receptor tyrosine kinase (RTK) array and phospho-tyrosine kinase array to explore the mechanism of the combined therapy. Western blotting, proximity ligation assay, and immunoprecipitation assay were also performed for validation. <B><I>Results:</I></B> Melatonin synergized with sorafenib to suppress the growth of PDAC both <I>in vitro</I> and <I>in vivo</I>. The effect was due to increased apoptosis rate of PDAC cells that was accompanied by mitochondria dysfunction. The enhanced anticancer efficacy by the co-treatment could be explained by blockade of PDGFR-β/STAT3 signaling pathway and melatonin receptor (MT)-mediated STAT3. <B><I>Conclusions:</I></B> Melatonin reinforces the anticancer activity of sorafenib by downregulation of PDGFR-β/STAT3 signaling pathway and melatonin receptor (MT)-mediated STAT3. The combination of the two agents might be a potential therapeutic strategy for treating PDAC.</P>

Selonsertib Inhibits Liver Fibrosis via Downregulation of ASK1/ MAPK Pathway of Hepatic Stellate Cells

( Young-chan Yoon ),( Zhenghuan Fang ),( Ji Eun Lee ),( Jung Hee Park ),( Ji-kan Ryu ),( Kyung Hee Jung ),( Soon-sun Hong ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.6

Liver fibrosis constitutes a significant health problem worldwide due to its rapidly increasing prevalence and the absence of specific and effective treatments. Growing evidence suggests that apoptosis-signal regulating kinase 1 (ASK1) is activated in oxidative stress, which causes hepatic inflammation and apoptosis, leading to liver fibrogenesis through a mitogen-activated protein kinase (MAPK) downstream signals. In this study, we investigated whether selonsertib, a selective inhibitor of ASK1, shows therapeutic efficacy for liver fibrosis, and elucidated its mechanism of action in vivo and in vitro. As a result, selonsertib strongly suppressed the growth and proliferation of hepatic stellate cells (HSCs) and induced apoptosis by increasing Annexin V and TUNEL-positive cells. We also observed that selonsertib inhibited the ASK1/MAPK pathway, including p38 and c-Jun N-terminal kinase (JNK) in HSCs. Interestingly, dimethylnitrosamine (DMN)-induced liver fibrosis was significantly alleviated by selonsertib treatment in rats. Furthermore, selonsertib reduced collagen deposition and the expression of extracellular components such as α-smooth muscle actin (α-SMA), fibronectin, and collagen type I in vitro and in vivo. Taken together, selonsertib suppressed fibrotic response such as HSC proliferation and extracellular matrix components by blocking the ASK1/MAPK pathway. Therefore, we suggest that selonsertib may be an effective therapeutic drug for ameliorating liver fibrosis.

HS-104, a PI3K inhibitor, enhances the anticancer efficacy of gemcitabine in pancreatic cancer.

Jung, Kyung Hee,Yan, Hong Hua,Fang, Zhenghuan,Son, Mi Kwon,Lee, Hyunseung,Hong, Sungwoo,Hong, Soon-Sun Lychnia 2014 International journal of oncology Vol.45 No.1

<P>Gemcitabine has limited clinical benefits for pancreatic cancer patients. The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is important in cell proliferation and survival, and is frequently dysregulated in pancreatic cancer. To obtain insights into novel therapeutic strategies for treating pancreatic cancer, we investigated whether HS-104, a novel PI3K inhibitor, in combination with gemcitabine would show a synergistic effect in pancreatic cancer. We first evaluated the effect of gemcitabine alone or in combination with HS-104 on cell viability. When administered together, the two drugs synergistically inhibited the viability of AsPC-1 and PANC-1 cells, and decreased mitochondrial membrane potential, thereby inducing apoptosis. Compared to the treatment with either drug alone, the combination treatment resulted in apoptosis accompanied by increased levels of cleaved caspase-3 and Bax. These results were consistent with decreased expression of p-Akt, p-mTOR, p-Mek and p-Erk. Moreover, the combination treatment inhibited blood vessel formation in a Matrigel plug assay in mice. Furthermore, in?vivo, the combination significantly inhibited tumor growth and enhanced apoptosis by increasing the number of TUNEL-positive cells, and cleaved caspase-3 together with decreasing the expression of angiogenesis- and proliferation-related effectors such as CD34 and PCNA in tumor tissues, compared with each drug alone. Taken together, our study demonstrates that the combination of gemcitabine and HS-104 had a synergistic anticancer effect and inhibited the PI3K/Akt and RAF/Mek pathways on pancreatic cancers. On the basis of our results, we suggest that the combination of these two drugs may be considered as a new therapeutic regimen for treating pancreatic cancer.</P>

HS-173 as a novel inducer of RIP3-dependent necroptosis in lung cancer

Park, Jung Hee,Jung, Kyung Hee,Kim, Soo Jung,Yoon, Young-Chan,Yan, Hong Hua,Fang, Zhenghuan,Lee, Ji Eun,Lim, Joo Han,Mah, Shinmee,Hong, Sungwoo,Kim, You-Sun,Hong, Soon-Sun Elsevier 2019 Cancer letters Vol.444 No.-

<P><B>Abstract</B></P> <P>Necroptosis is a form of regulated necrotic cell death mediated by receptor-interacting kinase 3 (RIP3). Recently, necroptosis has gained attention as a novel alternative therapy to target cancer cells. In this study, we screened several chemotherapeutics used in preclinical and clinical studies, and identified a drug HS-173 that induces RIP3-mediated necroptosis. HS-173 decreased the cell survival in a dose-dependent manner in RIP3-expressing lung cancer cells, compared to the cells lacking RIP3. Also, the cell death induced by HS-173 was rescued by specific necroptosis inhibitors such as necrostatin-1 and dabrafenib. Additionally, HS-173 increased the phosphorylation of RIP3 and MLKL, which was decreased by necroptosis inhibitors, indicating that HS-173 activates RIP3/MLKL signaling in lung cancer cells. HS-173 increased the necroptotic events, as observed by the increased levels of HMGB1 and necroptotic morphological features. Furthermore, HS-173 inhibited the tumor growth by stimulation of necroptosis in mouse xenograft models. Our findings offer new insights into the role of HS-173 in inducing necroptosis by enhancing RIP3 expression and activating the RIP3/MLKL signaling pathway in lung cancer cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Necroptosis is a novel alternative therapy to target cancer cells. </LI> <LI> HS-173 induced necroptosis in lung cancer cells by enhancing the expression of RIP3 and activating RIP3/MLKL signaling pathway. </LI> <LI> The necroptotic events induced by HS-173 has been observed by the increased levels of HMGB1 and necroptotic morphological features. </LI> <LI> HS-173 inhibited the tumor growth by stimulation of necroptosis in mouse xenograft models. </LI> <LI> Our findings offer new insights into the role of HS-173 on inducing necroptosis through RIP3 activation in lung cancer cells. </LI> </UL> </P>

Systemic and Local Metabolic Alterations in Sleep-Deprivation-Induced Stress: A Multiplatform Mass-Spectrometry-Based Lipidomics and Metabolomics Approach

Yoon, Sang Jun,Long, Nguyen Phuoc,Jung, Kyung-Hee,Kim, Hyung Min,Hong, Yu Jin,Fang, Zhenghuan,Kim, Sun Jo,Kim, Tae Joon,Anh, Nguyen Hoang,Hong, Soon-Sun,Kwon, Sung Won American Chemical Society 2019 JOURNAL OF PROTEOME RESEARCH Vol.18 No.9

<P>Sleep deprivation (SD) is known to be associated with metabolic disorders and chronic diseases. Complex metabolic alterations induced by SD at omics scale and the associated biomarker candidates have been proposed. However, in vivo systemic and local metabolic shift patterns of the metabolome and lipidome in acute and chronic partial SD models remain to be elucidated. In the present study, the serum, hypothalamus, and hippocampus CA1 of sleep-deprived rats (SD rats) from acute and chronic sleep restriction models were analyzed using three different omics platforms for the discovery and mechanistic assessment of systemic and local SD-induced dysregulated metabolites. We found a similar pattern of systemic metabolome alterations between two models, for which the area under the curve (AUC) of receiver operating characteristic curves was AUC = 0.847 and 0.930 with the pseudotargeted and untargeted metabolomics approach, respectively. However, SD-induced systemic lipidome alterations were significantly different and appeared to be model-dependent (AUC = 0.374). Comprehensive pathway analysis of the altered lipidome and metabolome in the hypothalamus indicated the abnormal behavior of eight metabolic and lipid metabolic pathways. The metabolic alterations of the hippocampus CA1 was subtle in two SD models. Collectively, these results extend our understanding of the quality of sleep and suggest metabolic targets in developing diagnostic biomarkers for better SD control.</P> [FIG OMISSION]</BR>

KRAS targeting antibody synergizes anti-cancer activity of gemcitabine against pancreatic cancer

Kang, Yeo Wool,Lee, Ji Eun,Jung, Kyung Hee,Son, Mi Kwon,Shin, Seung-Min,Kim, Soo Jung,Fang, Zhenghuan,Yan, Hong Hua,Park, Jung Hee,Han, Boreum,Cheon, Min Ji,Woo, Min Gyu,Lim, Joo Han,Kim, Yong-Sung,Ho Elsevier 2018 Cancer letters Vol.438 No.-

<P><B>Abstract</B></P> <P>Pancreatic cancer exhibits an oncogenic KRAS mutation rate of ∼90%. Despite research and drug development efforts focused on KRAS, no targeted therapy has been clinically approved for the treatment of pancreatic cancer with KRAS mutation. Also, the efficacy of gemcitabine is poor due to rapidly acquired resistance. We developed RT11-i antibody, which directly targets the intracellularly activated GTP-bound form of oncogenic RAS mutants. Here, we investigated the combined effects of RT11-i and gemcitabine <I>in vitro</I> and <I>in vivo</I>, and the mechanism involved. RT11-i significantly sensitized pancreatic cancer cells to gemcitabine. Also, the co-treatment synergistically inhibited angiogenesis, migration, and invasion, and showed synergistic anticancer activity by inhibiting the RAF/MEK/ERK or PI3K/AKT pathways. Furthermore, co-treatment inhibited endothelial barrier disruption in tumor vessels, which is a critical step in vascular leakiness of metastasis, and improved vessel structural stability. Importantly, co-treatment significantly suppressed tumor growth in an orthotopic tumor model. Taken together, our findings show that RT11-i synergistically increased the antitumor activity of gemcitabine by inhibiting RAS downstream signaling, which suggests RT11-i and gemcitabine be viewed a potential combination treatment option for pancreatic cancer patients with KRAS mutation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Pancreatic cancer exhibits an oncogenic KRAS mutation rate of ∼90%. KRAS gene silencing increased gemcitabine sensitivity in pancreatic cancer. </LI> <LI> RT11-i antibody directly targets the intracellularly activated GTP-bound form of RAS after being internalized into cytosol. </LI> <LI> RT11-i significantly sensitized pancreatic cancer cells to gemcitabine, as evidenced by reduced cell growth. </LI> <LI> The co-treatment showed synergistic anticancer activity by inhibiting the RAF/MEK/ERK or PI3K/AKT pathways. </LI> <LI> RT11-i and gemcitabine could be a potential combination treatment option for pancreatic cancer patients with KRAS. </LI> </UL> </P>

PBT-6, a Novel PI3KC2γ Inhibitor in Rheumatoid Arthritis

( Juyoung Kim ),( Kyung Hee Jung ),( Jaeho Yoo ),( Jung Hee Park ),( Hong Hua Yan ),( Zhenghuan Fang ),( Joo Han Lim ),( Seong-ryul Kwon ),( Myung Ku Kim ),( Hyun-ju Park ),( Soon-sun Hong ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.2

Phosphoinositide 3-kinase (PI3K) is considered as a promising therapeutic target for rheumatoid arthritis (RA) because of its involvement in inflammatory processes. However, limited studies have reported the involvement of PI3KC2γ in RA, and the underlying mechanism remains largely unknown. Therefore, we investigated the role of PI3KC2γ as a novel therapeutic target for RA and the effect of its selective inhibitor, PBT-6. In this study, we observed that PI3KC2γ was markedly increased in the synovial fluid and tissue as well as the PBMCs of patients with RA. PBT-6, a novel PI3KC2γ inhibitor, decreased the cell growth of TNFmediated synovial fibroblasts and LPS-mediated macrophages. Furthermore, PBT-6 inhibited the PI3KC2γ expression and PI3K/ AKT signaling pathway in both synovial fibroblasts and macrophages. In addition, PBT-6 suppressed macrophage migration via CCL2 and osteoclastogenesis. In CIA mice, it significantly inhibited the progression and development of RA by decreasing arthritis scores and paw swelling. Three-dimensional micro-computed tomography confirmed that PBT-6 enhanced the joint structures in CIA mice. Taken together, our findings suggest that PI3KC2γ is a therapeutic target for RA, and PBT-6 could be developed as a novel PI3KC2γ inhibitor to target inflammatory diseases including RA.

Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer

( Ji Eun Lee ),( Min Gyu Woo ),( Kyung Hee Jung ),( Yeo Wool Kang ),( Seung-min Shin ),( Mi Kwon Son ),( Zhenghuan Fang ),( Hong Hua Yan ),( Jung Hee Park ),( Young-chan Yoon ),( Yong-sung Kim ),( Soo 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.3

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.