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Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2–derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2–induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens. Cancer Res; 77(16); 4305–16. ©2017 AACR.

Bladder cancer is a common malignancy with high recurrent rate, but targeted therapy other than immune checkpoint inhibitors is currently unavailable. Hence, there is an unmet medical need for the discovery of new therapeutic approach to bladder cancer. By investigating Oncomine database, the mRNA level of CK1 delta is higher in bladder cancer compared to normal tissue, which correlates with survival rate. The aim of this study is to develop new CK1 delta inhibitors and examine their therapeutic potential to bladder cancer as well as the pharmacological mechanisms. Cell viability, cell cycle progression, apoptosis, migration and downstream signaling pathway were analyzed. The results showed that treatment of CK1 delta inhibitors decreased cell viability and inhibited wnt/β-catenin pathway in bladder cancer cell lines. CK1 delta inhibitors increased the accumulation of sub-G1 phase by flow cytometry analysis, as well as the activation of caspase-3, 8, 9 and PARP cleavage by western blot, indicating the promotion of cell apoptosis. Meanwhile, necroptosis was also involved as evident by the rescuing effects by knocking down MLKL in bladder cancer cells. In conclusion, this study demonstrates that CK1 delta is a potential target for bladder cancer therapy in the future. Note: This abstract was not presented at the meeting. Citation Format: Yu-Chen Lin, Mei-chuan Chen, Jing-Ping Liou, Chun-Han Chen. Developing new therapeutic strategy to bladder cancer by targeting CK1 delta [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2939.

BPR0L075 is a novel synthetic compound discovered through research to identify new microtubule inhibitors. BPR0L075 inhibits tubulin polymerization through binding to the colchicine-binding site of tubulin. Cytotoxic activity of BPR0L075 in a variety of human tumor cell lines has been ascertained, with IC50 values in single-digit nanomolar ranges. As determined by flow cytometry, human cervical carcinoma KB cells are arrested in G2-M phases in a time-dependent manner before cell death occurs. Terminal deoxynucleotidyl transferase-mediated nick end labeling assay indicates that cell death proceeds through an apoptotic pathway. Additional studies indicate that the effect of BPR0L075 on cell cycle arrest is associated with an increase in cyclin B1 levels and a mobility shift of Cdc2 and Cdc25C. The changes in Cdc2 and Cdc25C coincide with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. Furthermore, phosphorylated forms of Bcl-2, perturbed mitochondrial membrane potential, and activation of the caspase-3 cascade may be involved in BPR0L075-induced apoptosis. Notably, several KB-derived multidrug-resistant cell lines overexpressing P-gp170/MDR and MRP are resistant to vincristine, paclitaxel, and colchicine but not to BPR0L075. Moreover, BPR0L075 shows potent activity against the growth of xenograft tumors of the gastric carcinoma MKN-45, human cervical carcinoma KB, and KB-derived P-gp170/MDR-overexpressing KB-VIN10 cells at i.v. doses of 50 mg/kg in nude mice. These findings indicate BPR0L075 is a promising anticancer compound with antimitotic activity that has potential for management of various malignancies, particularly for patients with drug resistance.

Ovarian cancer is one of the leading causes of death in women with gynecological malignancy in the United States. About 70% of ovarian cancer cases are diagnosed at an advanced stage resulting in poor survival rate. In the present study, we provide the data showing that MPT0G066, a novel synthetic arylsulfonamide compound, inhibited cell growth and viability in human ovarian cancer cell lines as evidenced by sulphorodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Cell cycle distribution was also determined by flow cytometry, the data revealed that MPT0G066 induced cell cycle arrest at multipolyploidy (MP) phase (SKOV3 cells) or at G2/M phase (A2780 cells) in 24 hours and ultimately increased the cell population in sub-G1 phase in 48 hours. Moreover, in vitro tubulin polymerization assay, in situ labeling of β-tubulin and western blot analysis showed that MPT0G066, similar to colchicine and vincristine, promoted tubulin depolymerization and altered the expression of G2/M cell cycle regulatory proteins. Mechanistically, MPT0G066 induced JNK activation and altered Bcl-2 family proteins by increasing the expression of p-Bcl-2, Bax, Bim, Puma and decreasing the level of Bcl-2 and Mcl-1. Disruption of mitochondrial proteins triggered intrinsic apoptotic pathways through the cleavage of caspase-3, -7, -9, and poly (ADP-ribose) polymerase (PARP). Moreover, treatment with SP600125, a JNK inhibitor, abolished the effects of MPT0G066 on cell viability, Bcl-2 family proteins and apoptotic cell death. Finally, we used xenograft mouse model to demonstrate that MPT0G066 is able to suppress the growth of ovarian carcinoma A2780 cells and potentiated the antineoplastic effects of cisplatin in vivo. Immunohistochemistry data also confirmed MPT0G066-induced JNK activation in tumor sections. In summary, these results suggested that MPT0G066 could disrupt microtubule dynamics, and lead to cell cycle arrest at MP phase or G2/M phase. MPT0G066 induced JNK activation and altered Bcl-2 family proteins, which ultimately caused apoptosis through the intrinsic apoptotic pathways. These finding indicated that MPT0G066 is a potential anticancer agent worthy for further development and may foster novel treatment for patients with ovarian cancer. Citation Format: Chun-Han Chen, Ya-Chi Li, Li-Hsun Chang, Jing-Ping Liou, Shiow-Lin Pan, Che-Ming Teng. MPT0G066, a novel microtubule-destabilizing agent, induces cell apoptosis and potentiates antineoplastic effects of cisplatin in human ovarian cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4494. doi:10.1158/1538-7445.AM2013-4494

Identification of a single agent that is able to target tumor cells, rapidly destroy tumor vasculature and inhibit angiogenesis could be an ideal approach for targeting solid tumors. We recently discover a novel sulfonamide compound, 7-aryl-indoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine binding site of tubulin. MPT0B098 is active against various human cancer cell growth with IC50 values ranged from 70-300 nM. Notably, HUVEC cells exhibit less susceptibility to the inhibitory effect of MPT0B098 with an IC50 of 510 nM. In addition, MPT0B098 exhibits no cross resistance with vincristine, paclitaxel, etoposide and camptothecin-resistant cell lines. Interestingly, MPT0B098 is still active toward cells (KB L30) with beta1-tubulin mutation. MPT0B098 arrests cells in G2/M phase and subsequently induces cell apoptosis through the caspase-dependent apoptotic pathway. In addition, using sub-lethal dose, MPT0B098 effectively suppressed to the tube formation and migration of HUVECs induced by VEGF. The expression levels of HIF-1alpha and VEGF were significantly inhibited in a concentration-dependent manner by MPT0B098 under hypoxic condition. Furthermore, HIF-1alpha-regulated genes, including cathepsin D, PDGF, VEGF, and VHL, were found to be down-regulated by MPT0B098 in A549 cells. Moreover, the decrease of the amount of HuR, a HIF-1alpha mRNA stability protein, translocated from nuclear to cytoplasm and suppression of AKT activity were coincided with decreased amount of HIF-1alpha mRNA by MPT0B098 treatment under hypoxia condition. MPT0B098 significantly suppressed tumor growth and microvessel density of tumor in H460 and KB-Vin10 xenografted mouse model. Taken together, our results indicate that MPT0B098 is a promising anticancer drug with potential for the treatment of human malignancies. (The study was supported by grants of DOH99-TD-C-111-004 from Department of Health and CA-099-PP-02 from National Health Research Institutes, Taiwan, R.O.C.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4461. doi:10.1158/1538-7445.AM2011-4461