Inorganic arsenic, a human carcinogen, is also an effective therapeutic agent for acute promyelocytic leukemia. Arsenic exposure induces numerous deletenious effects such as oxidative damages, chromosome aberrations, cell cycle arrest, and apoptosis in a variety of human cells. Unfortunately, the mechanism(s) of how arsenic induces apoptosis remains unclear. However, these cellular responses are greatly dependent on changes in gene expression. A recently developed colorimetric cDNA microarray technique allows us to investigate the changes in gene expression profiles of cells exposed to toxic substances. In this study, cDNA microarray membranes with 568 human genes were used to examine the transcripition profiling changes in human fibroblasts treated with 5 μM sodium arsenite for 0 to 24 h. Preliminary results showed that mRNA levels of heat shock proteins 60and 70 were time dependently increased in HFW cells, indicating the reliability of our assay system. Furthermore, mRNA levels of several cell cyclerelated genes, such as cyclin B1, cyclin G1 and DNA topoisomerase 11 d, were also elevated at late stage (12 -24 h) of arsenite treatment, confirming that arsenite could disturb cell cycle progression. mRNA levels of transcription factors and transcription regulators such as heat shock transcription factor, Egr-1, ATF2, GADD153, Zfp36, and SW1/SNF were also time-dependently increased in arsenite-treated HFW cells., In addition, the mRNA levels of several p53-activated genes such as p21/Cip, MDM-2, cyclin B1, cyclin G1, and GADD45 were up regulated after arsenite treatment, indicating p53 was activated in arsenite-treated HFW cells. These present results indicated that numerous specific transcription factors and regulators controlling cellular stress responses and cell cycle progression will be activated in cells responsible for toxic substance exposure.
Abstract Lung cancer is the most common cancer worldwide. Platinum-based combination chemotherapy is one of first line treatments for patients with lung cancer. Most of the cytotoxic drugs are targeting DNA, interfere with DNA synthesis, and triggering DNA damage response (DDR). Since DDR usually activates important defensive pathways to repair damaged DNA, DDR is known as a key factor determining the outcome of chemotherapy. Among them, RAD51, playing a central role in homologous recombination (HR) DNA repair, has been shown to interfere with the prognosis of patients treated with chemoradiotherapy. Since we have demonstrated that inhibition of RAD51 nuclear focus formation synergistically enhances the anticancer activity of cisplatin, we further screened purified natural products in order to find products with activity to inhibit RAD51 nuclear focus formation. In the present study, we found that a green tea catechin derivative, the (-)-Gallocatechin gallate (GCG) has potent inhibitory activity against RAD51 nuclear focus formation in cisplatin-treated H460 cells. The in vitro cytotoxicity assay showed that the combination of cisplatin or irinotecan with GCG significantly increases the sensitivity of H460 cells to these DNA damage agents. We also evaluated the anti-tumor growth activity of cisplatin or irinotecan in combination with GCG using H460 xenografts. Our results showed that cisplatin and irinotecan suppresses tumor growth by 17.6% and 33.8%, while in combination with GCG suppresses tumor growth by 52.2% and 68.9%, respectively. We further demonstrated that GCG is able to inhibit cisplatin-induced ATM and Chk2 phosphorylation. Together, our results suggest that GCG may interfere with ATM-Chk2 pathway and hence suppress RAD51 nuclear focus formation and DNA repair activities. Citation Format: Ming-Hsi Wu, Lie-Chwen Lin, Te-Chang Lee. Augmentation of response to therapeutic agents by (-)-gallocatechin gallate through inhibition of RAD51 nuclear translocation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3733.
Abstract Angiogenesis plays a critical role in sustaining the microenvironment, growth, and metastatic potential of a variety of tumors, such as lung cancer, colorectal cancer, and renal cancer. However, the rapid development of resistance to anti-angiogenesis agents has limited the clinical benefits. To improve the therapeutic efficacy, the designed dual functional inhibitors, composed of benzophthalazine (anti-angiogenesis moiety) and bis(hydroxymethyl)pyrrole (DNA interstrand crosslinking moiety), were synthesized. We first demonstrated that 1,2-bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazines displayed dual functions, inducing DNA crosslinking and inhibiting angiogenesis. By aid of DIVAA, we confirmed the in vivo anti-angiogenetic activity. They were cytotoxic to a panel of cancer cell lines, including leukemia, colorectal, renal, and lung cancer cells. Among them, small cell lung cancer (SCLC) cells were the most susceptible cells with the IC50 values ranged from subnanomolar to micromolar. Significantly, we observed tumor suppression by treatment of compound 8 in a given formulation at the dose of 20 mg/kg (10 times in 2 weeks) in SCLC H526, squamous lung cancer H520 and renal cancer 786-O xenograft models. In addition, orally admission of 60 mg/kg compound 8 daily for 14 days was also more potent than cisplatin in suppression of growth of SCLC H526 xenografts. Importantly, compound 8 at the dose given did not cause body weight lost. In summary, our results indicate that bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine hybrids are potent than anticancer agents against a wide spectrum of cancers. They deserve our further development. Citation Format: Tai-Lin Chen, Vicky Jain, Anilkumar S. Patel, Yi-Wen Lin, Tsann-Long Su, Te-Chang Lee. Discovery of bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives as orally bioavailable antitumor agents with anti-angiogenic and DNA cross-linking activities [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A002. doi:10.1158/1535-7163.TARG-19-A002
The induction of heme oxygenase-1 (HO-1) has been shown to have therapeutic potential in experimental models of hepatitis and liver fibrosis, which are closely related to liver cancer. In humans, HO-1 induction is transcriptionally modulated by the length of a GT-repeat [(GT)n] in the promoter region. We aimed to investigate the effect of HO-1 (GT)n variants on liver cancer in a human population. We determined the HO-1 genotype in 1153 study subjects and examined their association with liver cancer risk during a 15.9-year follow-up. Allelic polymorphisms were classified as short [S, <27 (GT)n] or long [L, ≥27 (GT)n]. Newly developed cancer cases were identified through linkage to the National Cancer Registry of Taiwan. Multivariate Cox regression analysis was used to evaluate the effect of the HO-1 (GT)n variants. Alpha-fetoprotein (AFP) and cirrhosis history were also examined. The S/S genotype was found to be significantly associated with liver cancer risk, compared to the L/S and L/L genotypes. The S/S genotype group also had a higher percentage of subjects with abnormal AFP levels than other groups. There were significant percentages of cirrhosis among groups who carried S-alleles. Our findings indicate that short (GT)n variants in the HO-1 gene may confer susceptibility to rather than protection from liver cirrhosis/cancer.
// Li-Fang Lin 1 , Ming-Hsi Wu 1 , Vijaya Kumar Pidugu 1, 2 , I-Ching Ho 1 , Tsann-Long Su 1 and Te-Chang Lee 1, 2, 3 1 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan 2 Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University, Academia Sinica, Taipei 11529, Taiwan 3 Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan Correspondence to: Te-Chang Lee, email: bmtcl@ibms.sinica.edu.tw Keywords: P-glycoprotein, multidrug resistance, Cbp-Csk-Src cascade, DNA repair proteins Received: October 07, 2016 Accepted: January 24, 2017 Published: February 03, 2017 ABSTRACT Recent studies have demonstrated that P-glycoprotein (P-gp) expression impairs DNA interstrand cross-linking agent-induced DNA repair efficiency in multidrug-resistant (MDR) cells. To date, the detailed molecular mechanisms underlying how P-gp interferes with Src activation and subsequent DNA repair activity remain unclear. In this study, we determined that the C-terminal Src kinase-binding protein (Cbp) signaling pathway involved in the negative control of Src activation is enhanced in MDR cells. We also demonstrated that cells that ectopically express P-gp exhibit reduced activation of DNA damage response regulators, such as ATM, Chk2, Braca1 and Nbs1 and hence attenuated DNA double-strand break repair capacity and become more susceptible than vector control cells to DNA interstrand cross-linking (ICL) agents. Moreover, we demonstrated that P-gp can not only interact with Cbp and Src but also enhance the formation of inhibitory C-terminal Src kinase (Csk)-Cbp complexes that reduce phosphorylation of the Src activation residue Y416 and increase phosphorylation of the Src negative regulatory residue Y527. Notably, suppression of Cbp expression in MDR cells restores cisplatin-induced Src activation, improves DNA repair capacity, and increases resistance to ICL agents. Ectopic expression of Cbp attenuates cisplatin-induced Src activation and increases the susceptibility of cells to ICL agents. Together, the current results indicate that P-gp inhibits DNA repair activity by modulating Src activation via Cbp-Csk-Src cascade. These results suggest that DNA ICL agents are likely to have therapeutic potential against MDR cells with P-gp-overexpression.
Abstract Most ureteral tumors are transitional cell neoplasms. Neuroendocrine tumors of the genitourinary tract are extremely rare. To our knowledge, only one ureteral carcinoid tumor has been reported before. We report a second case of ureteral carcinoid tumor found in a 70‐year‐old female.
Abstract Small cell lung cancer (SCLC) is an aggressive type of lung cancer and accounts for 10% to 15% of all lung cancer cases. The malignancy has a greater tendency to be widely disseminated by the time of diagnosis as well as to develop early resistance to conventional treatments, a cure is difficult to achieve. The current standard therapy for SCLC treatment, either with monotherapy (platinum based drugs) or combination therapy (e.g., cisplatin with irinotecan or topotecan), was shown to cause serious side effects and inevitably evoke drug resistance in a short time period. We have recently synthesized a series of novel bis(hydroxymethyl)indolizino[8,7-b]indole hybrids by fusing β-carboline and bis(hydroxymethyl)pyrrole moieties for antitumor evaluation. These hybrid molecules displayed diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Our results also showed that they significantly inhibited the cell growth of various human tumor cell lines. Of the tested tumor cell lines, the SCLC cells (H526 and H211) were the most susceptible to compounds BO-2239 and BO-2329. These hybrids induced cell cycle arrest at the G2/M phase and triggered tumor cell apoptotic death. Intriguingly, the substituent at N11 (H or Me) played a critical role in modulating Topo II inhibition and DNA cross-linking. Compared to the compounds with N11-Me group, derivatives having N11-H group profoundly increased Topo II inhibition activity but reduced DNA cross-linking activity. Among these hybrids, BO-2239 (with N11-H) was as potent as irinotecan, but more effective than cisplatin, in nude mice bearing SCLC H526 xenografts. Accordingly, hybrid BO-2239 may be further developed as a potential agent for the treatment of SCLC. Citation Format: Sue-Ming Chang, Ming-Hsi Wu, Hima Bindu Pidugu, Tsann-Long Su, Te-Chang Lee. Novel indolizino[8,7-b]indole hybrids with potent activity against small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5126. doi:10.1158/1538-7445.AM2017-5126
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