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CD24 is a well-characterized breast cancer (BC) stem cell (BCSC) marker. Primary breast tumor cells having CD24-negativity together with CD44-positivity is known to maintain high metastatic potential. However, the functional role of CD24 gene in triple-negative BC (TNBC), an aggressive subtype of BC, is not well understood. While the significance of CD24 in regulating immune pathways is well recognized in previous studies, the significance of CD24 low expression in onco-signaling and metabolic rewiring is largely unknown. Using CD24 knock-down and over-expression TNBC models, our in vitro and in vivo analysis suggest that CD24 is a tumor suppressor in metastatic TNBC. Comprehensive in silico gene expression analysis of breast tumors followed by lipidomic and metabolomic analyses of CD24-modulated cells revealed that CD24 negativity induces mitochondrial oxidative phosphorylation and reprograms TNBC metabolism toward the fatty acid beta-oxidation (FAO) pathway. CD24 silencing activates PPARα-mediated regulation of FAO in TNBC cells. Further analysis using reverse-phase protein array and its validation using CD24-modulated TNBC cells and xenograft models nominated CD24-NF-κB-CPT1A signaling pathway as the central regulatory mechanism of CD24-mediated FAO activity. Overall, our study proposes a novel role of CD24 in metabolic reprogramming that can open new avenues for the treatment strategies for patients with metastatic TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oncogenic KRAS G12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRAS G12D -mediated ADM and early PDAC intervention remains unknown. In the current study, we investigated the role of ANGPTL4 in KRAS G12D -induced ADM, PanIN formation, and PDAC maintenance. We found that ANGPTL4 was highly expressed in human and mouse ADM lesions and contributed to the promotion of KRAS G12D -driven ADM in mice. Consistently, ANGPTL4 rapidly induced ADM in three-dimensional culture of acinar cells with KRAS mutation and formed ductal cysts that silenced acinar genes and activated ductal genes, which are characteristic of in vivo ADM/PanIN lesions. We also found that periostin works as a downstream regulator of ANGPTL4-mediated ADM/PDAC. Genetic ablation of periostin diminished the ADM/PanIN phenotype induced by ANGPTL4. A high correlation between ANGPTL4 and periostin was confirmed in human samples. These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

KRAS mutation is associated with the progression and growth of pancreatic cancer and contributes to chemo-resistance, which poses a significant clinical challenge in pancreatic cancer. Here, we developed a RT22-ep59 antibody (Ab) that directly targets the intracellularly activated GTP-bound form of oncogenic KRAS mutants after it is internalized into cytosol by endocytosis through tumor-associated receptor of extracellular epithelial cell adhesion molecule (EpCAM) and investigated its synergistic anticancer effects in the presence of gemcitabine in pancreatic cancer. We first observed that RT22-ep59 specifically recognized tumor-associated EpCAM and reached the cytosol by endosomal escape. In addition, the anticancer effect of RT22-ep59 was observed in the high-EpCAM-expressing pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells, but it had little effect on the low-EpCAM-expressing pancreatic cancer cells. Additionally, co-treatment with RT22-ep59 and gemcitabine synergistically inhibited cell viability, migration, and invasion in 3D-cultures and exhibited synergistic anticancer activity by inhibiting the RAF/ERK or PI3K/AKT pathways in cells with high-EpCAM expression. In an orthotopic mouse model, combined administration of RT22-ep59 and gemcitabine significantly inhibited tumor growth. Furthermore, the co-treatment suppressed cancer metastasis by blocking EMT signaling in vitro and in vivo. Our results demonstrated that RT22-ep59 synergistically increased the antitumor activity of gemcitabine by inhibiting RAS signaling by specifically targeting KRAS. This indicates that co-treatment with RT22-ep59 and gemcitabine might be considered a potential therapeutic strategy for pancreatic cancer patients harboring KRAS mutation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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 in vitro and in vivo, 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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 c 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 in vitro, as well as ex vivo tumor spheroid models, resulting in potent induction of apoptosis. Importantly, KK5101 also significantly attenuated tumor growth of in vivo 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Pancreatic cancer is a highly lethal disease for which limited therapeutic options are available. Pancreatic cancer exhibits a pronounced collagen-rich stromal reaction, which induces chemoresistance by inhibiting drug diffusion into the tumor. Complementary treatment with oncolytic virus such as an oncolytic adenovirus expressing relaxin (YDC002) is an innovative treatment option for combating chemoresistant pancreatic cancer. Here, we examined the ability of combined treatment with gemcitabine and YDC002, which degrades extracellular matrix (ECM), to efficiently treat chemoresistant and desmoplastic pancreatic cancer. Gemcitabine alone exhibited similarly low cytotoxicity toward pancreatic cancer cells throughout the concentration range (1-50 μM) used, whereas the combination of YDC002 and a subtherapeutic dose of gemcitabine (0.01-0.05 μM) resulted in potent anticancer effects through effective induction of apoptosis. Importantly, YDC002 combined with gemcitabine significantly attenuated the expression of major ECM components including collagens, fibronectin, and elastin in tumor spheroids and xenograft tumors compared with gemcitabine alone, resulting in potent induction of apoptosis, gemcitabine-mediated cytotoxicity, and an oncolytic effect through degradation of tumor ECM. Our results demonstrate that YDC002 can selectively degrade aberrant ECM and attenuate the ECM-induced chemoresistance observed in desmoplastic pancreatic tumor, resulting in a potent antitumor effect through effective induction of apoptosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Pancreatic cancer is known to have low 5-year survival rate and poor response to treatment. In this study, we synthesized HS-527, a new PI3-kinase inhibitor, and investigated not only its anticancer activity, but also its mechanism of action in pancreatic cancer cells. HS-527 had higher specificity for PI3K than other kinases and inhibited PI3K/Akt signaling pathway by down-regulating Akt and P70S6K. And HS-527 inhibited the cell growth and proliferation of the pancreatic cancer in a time- and dose-dependent manner, with greater activity than gemcitabine. Even HS-527 showed lower cytotoxicity than gemcitabine in normal cells. When treated with HS-527, the cancer cells appeared apoptotic, increasing the expression of cleaved PARP, cleaved caspase-3, and Bax. Furthermore, HS-527 showed an anti-angiogenic activity by decreasing the expression of HIF-1α and VEGF, and inhibited the migration of endothelial cells, and the formation of new blood vessel in mouse Matrigel plug assay. In this study, we found that HS-527 showed anti-cancer activity through an inhibition of the PI3K/Akt pathway in pancreatic cancer cells, suggesting that HS-527 could be used as a promising therapeutic agent for pancreatic cancer., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Imatinib is a selective breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitor (TKI) that has significantly improved the prognosis of patients with chronic myeloid leukemia (CML). However, T315I gene mutations of the BCR-ABL kinase domain have been shown to confer resistance to imatinib. In the present study, we synthesized a novel BCR-ABL inhibitor, HS-438, and identified its anti-leukemic effects in vitro and in vivo. We found that HS-438 strongly inhibited the expression of BCR-ABL signaling pathways in wild-type BCR-ABL (BaF3/WT) cells as well as T315I-mutated BCR-ABL (BaF3/T315I) cells with resistance to imatinib. HS-438 induced cell cycle arrest, particularly during the G0/G1 cell cycle phase, and induced apoptosis. In BaF3/T315I xenograft models, HS-438 significantly delayed tumor growth, unlike imatinib. In summary, we suggest that HS-438 may be a novel drug candidate with the therapeutic potential to target BCR-ABL and overcome imatinib resistance in patients with CML., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

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., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been reported to be involved in tumorigenesis and metastatic progression. We synthesized a novel triazolopyridazine derivative KRC-327 which selectively targets the c-Met. When we performed receptor tyrosine kinases (RTKs) array with 42 different phosphorylated-RTKs, KRC-327 strongly inhibited expression of activated c-Met in MKN-45 cancer cells. This was confirmed by immunofluorescence staining. Also, KRC-327 decreased the expression of Gab1, Akt, signal transducer and activator of transcription 3 (STAT3) and Erk, down-stream signals of c-Met. KRC-327 strongly suppressed the growth of c-Met over-expressed cancer cells (MKN-45, SNU-638, SNU-5), while not in c-Met absent cancer cell lines (MKN-1, SNU-1). Furthermore, KRC-327 effectively induced cell cycle arrest, especially G0/G1 arrest by increasing expression of p21, p27 and decreasing that of cyclin D1. In the ligand-induced functional studies, KRC-327 inhibited proliferation of HGF-stimulated BxPC-3 cells, the migration of HGF-stimulated AGS cancer cells, and suppressed colony formation in HGF-stimulated U-87MG cells. In xenograft animal models, KRC-327 significantly not only delayed tumor growth but also suppressed phosphorylation of c-Met and its signaling cascades as well as proliferation. Taken together, these results demonstrate that KRC-327 selectively targets c-Met, resulting in inhibition of cell growth and proliferation. Therefore, we suggest that KRC-327 may be a novel drug candidate with the therapeutic potential of targeting c-Met in human cancer., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

The RAF/MEK/ERK and PI3K/AKT pathways are highly implicated in the development of pancreatic cancer. The principal objective of this study was to assess the synergic effect between Sorafenib (a RAF inhibitor) and HS-173 (a novel PI3K inhibitor) to gain insight into novel therapeutic strategies for treating pancreatic cancer. We first investigated the cytotoxic effect of co-treatment with Sorafenib and HS-173 using the Calcusyn program. Combined treatment of the two drugs synergistically inhibited the viability of Panc-1 cells (combination index<1). Concomitantly, the co-treatment induced G2/M arrest and increased apoptosis with the loss of mitochondrial membrane potential. Apoptosis resulting from the co-treatment was accompanied by increased levels of cleaved caspase-3 and PARP as well as greater numbers of TUNEL-positive apoptotic cells compared to treatment with either drug alone. Furthermore, combined treatment with these drugs decreased the expression of HIF-1α and VEGF which play an important role in angiogenesis. This anti-angiogenic effect was confirmed by the suppressed tube formation of VEGF-induced human umbilical vein endothelial cells and inhibition of blood vessel formation in a Matrigel plug assay in mice. Taken together, our study demonstrates that combined treatment with Sorafenib and HS-173 has a synergistic anti-cancer effect on pancreatic cancer cells, indicating that simultaneously targeting the RAF/MEK and PI3K/AKT pathways can induce a synergistic inhibitory effect on pancreatic cancers in which both pathways are activated. Based on the observations from our study, we suggest that the combined administration of these two drugs may be considered to be a new therapeutic regimen for treating pancreatic cancer., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is an essential step for the formation and growth of tumors in humans. HS-106 is an imidazopyridine derivative that inhibits the kinase activity of PI3K by binding to the ATP-binding cleft. We found that this compound suppressed breast cancer cell proliferation and induced apoptosis by specifically inhibiting the activity of target proteins in the PI3K/Akt/mTOR signaling pathway. Cell cycle analysis revealed that treatment with HS-106 resulted in cell cycle arrest at the G(2)/M phase due to up-regulation of p-cdc25 and down-regulation of cyclin B1. Also, HS-106 induced apoptosis by increasing the levels of cleaved caspase-3 and cleaved PARP. In addition, chromatin condensation and apoptotic bodies were detected in HS-106-treated breast cancer cells. Furthermore, HS-106 decreased the expression of hypoxia-inducible factor 1α (HIF-1α), and inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs) in vitro and blood vessel formation in an in vivo Matrigel plug assay. These results show that HS-106 may be an effective novel therapeutic candidate in clinical trials as a potential treatment for human breast cancers or other advanced malignancies with aberrant PI3K/Akt/mTOR signaling., (Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.)

As the activation of phosphatidylinositol 3-kinase (PI3K) is associated with a wide variety of human malignancies, it is emerging as an attractive target for cancer treatment. In this study we synthesized a novel PI3Kα inhibitor, IPD-196 [ethyl 6-(5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate], and evaluated its anticancer effects on human hepatocellular carcinoma (HCC) cells. IPD-196 effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR, p70S6K, and 4E-BP1, and its antiproliferative effect was more potent than that of sorafenib or LY294002. It also induced cell cycle arrest at the G0/G1 phase as well as apoptosis by increasing the proportion of sub-G1 apoptotic cells, and the levels of cleaved PARP, caspase-3, and caspase-9. Furthermore, it decreased the expression of HIF-1α and VEGF in Huh-7 cells, and inhibited tube formation and migration of human umbilical vein endothelial cells, which was confirmed by a Matrigel plug assay in mice. Taken together, IPD-196 exhibited its anticancer activity through disruption of the PI3K/Akt pathway that caused cell cycle arrest, apoptosis induction, and inhibition of angiogenesis in human HCC cells. We therefore suggest that IPD-196 may be a potential candidate drug for targeted HCC therapy., (Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.)

We synthesized a novel imidazopyridine analogue, a PI3Kα inhibitor HS-173 and investigated anti-cancer capacity in human cancer cells. HS-173 inhibited the PI3K signaling pathway, and showed anti-proliferative effects on cancer cells. Also, HS-173 induced cell cycle arrest at the G(2)/M phase and apoptosis. In addition, HS-173 decreased the expression HIF-1α and VEGF which play an important role in angiogenesis. This effect was confirmed by the suppression of tube formation and migration assay in vitro. Furthermore, HS-173 diminished blood vessel formation in the Matrigel plug assay in mice. Therefore, HS-173 is considered as a novel drug candidate to treat cancer patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently instigates tumorigenesis leading to hepatocellular carcinoma (HCC). We synthesized N-(5-(3-(3-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (HS-104), a novel PI3K inhibitor, and investigated its in vitro anticancer effect and in vivo capacity in an animal xenograft model. The inhibition of cell growth by HS-104 revealed that it was effective against HCC cell lines. Also, the activation of the AKT/mTOR signal cascade was inhibited by HS-104 treatment in a dose dependent manner. Flow cytometry analysis showed an accumulation of HCC cells in the G2/M phase with concomitant loss of cells in the S phase. The apoptotic effect of HS-104 was accompanied by increased evidence of cleaved caspase-3 and PARP, as well as DNA fragmentation. In angiogenesis studies, HS-104 inhibited the tube formation of vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from a rat aortic ring, ex vivo, and blood vessel formation in the Matrigel plug assay in mice. HS-104 inhibited the expression of the downstream proteins of PI3K including p-AKT, p-mTOR and p-p70S6K in VEGF-induced HUVECs. In the xenograft animal model, HS-104 significantly delayed tumor growth in a dose dependent manner and suppressed the expression of PCNA, CD34 and cleaved caspase-3 in tumor tissue. These studies show that HS-104 inhibited the PI3K/AKT/mTOR signaling pathway resulting in cell growth/angiogenesis inhibition and apoptosis induction. Therefore, HS-104 is considered as a novel drug candidate for the treatment of HCC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival of human cancers. As PI3K is active in many cancer patients, resulting in cancer development and progression, we developed an azaindole derivative, HS-116 as a novel PI3K inhibitor. This study aimed to clarify the anticancer effect of HS-116 in human hepatocellular carcinoma (HCC). To identify the effect of HS-116 on HCC cells, a PI3K assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blotting were conducted. IC(50) of HS-116 for PI3Kα was 31nM, and it effectively suppressed the phosphorylation of PI3K downstream factors such as AKT, mTOR, p70S6K, and 4EBP1. Also, HS-116 induced apoptosis by increasing the proportion of sub-G1 apoptotic cells from 1.8% to 35% and increasing the expressions of Bax, cleaved-caspase-3, and cleaved-PARP as well as decreasing the expression of Bcl-2. In addition, chromatin condensation and apoptotic bodies were detected in HS-116-treated HCC cells. Furthermore, HS-116 decreased protein expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), and inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVECs). In vivo, the ability of mice to vascularize subcutaneously implanted Matrigel plugs was diminished when the mice were treated with HS-116. These results show that HS-116 inhibits the PI3K/AKT/mTOR pathway via apoptosis and anti-angiogenesis in HCC cells. We suggest that HS-116 may be an effective novel therapeutic candidate against HCC., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most common malignancies, yet there have been no significant advances in effective therapeutics. In this study, HS-113 was synthesized as a novel compound, N-(5-(2-bromobenzyl) thiazole-2-yl) benzofuran-2-carboxamide and its cytotoxic activity and anti-cancer effect were examined in human HCC cells. HS-113 strongly suppressed growth of HCC cells in a dose-dependent manner, induced apoptosis by increasing the proportion of sub-G1 apoptotic cells, and caused cell cycle arrest at G0/G1 phase. Also, HS-113 increased the expression of p27 and decreased that of cyclin D1 associated with cell cycle arrest. Apoptosis by HS-113 was confirmed by DAPI and TUNEL staining, and the increases of the cleaved PARP and caspase-3 were observed. Furthermore, HS-113 decreased protein expression of HIF-1α and secretion of VEGF, and inhibited the tube formation of HUVECs. These results showed that HS-113 not only inhibited cell growth and angiogenesis, but also induced apoptosis of human HCC cells. We suggest that HS-113 may be a potential candidate for cancer therapy against HCC., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Since its introduction 6 years ago, imatinib mesylate, a selective tyrosine kinase inhibitor, has been a phenomenon in treating chronic myelogenous leukemia (CML) with remarkably superior cytogenetic and molecular response rates at all stages of CML followed by longer progression free survival. Despite its extraordinarily high efficacy, adverse effects of imatinib mesylate such as edema, liver toxicity and fluid retention syndromes have been reported. Here we, for the first time, report development of heart failure in patients on imatinib mesylate medication and the possibility of brain natriuretic peptide (BNP) as a potential diagnostic (or predicting) marker for heart failure. Since plasma BNP levels in the two patients were exceptionally high, we then explored the possibility of genetic association of BNP with the development of heart failure to find no positive association.