Leroy Liu Professor UMDNJ Department of Pharmacology UMDNJ-Robert Wood Johnson Medical School 675 Hoes Lane Piscataway. NJ 08854 (732) 235-4592 FAX - 4073 lliu@umdnj.edu

Tumorigenesis. topoisomerases. telomere regulation and senescence. DNA damage and repair

Our main research interest is in the areas of cancer biology and cancer pharmacology. The following specific research projects are currently being conducted in this laboratory:

1. Studies on topoisomerase I-mediated DNA damage. Top I has been firmly established as a highly effective new molecular target for antitumor drugs such as camptothecins (CPTs) (e.g. irinotecan and topotecan). CPTs kill tumor cells by trapping a key covalent Top I-DNA reaction intermediate. the reversible cleavable complex. In addition to CPTs and other Top I-directed drugs. DNA structural modifications (e.g. benzo[a]pyrene-DNA adducts. UV adducts. oxidative modifications and AraC-substituted DNA) have been shown to cause trapping of Top I cleavable complexes. Despite the importance of Top I cleavable complexes as a new type of cellular lesion. our current understanding of repair/processing of Top I cleavable complexes is still quite limited. We have identified two novel molecular events downstream of the Top I cleavable complex. ubiquitin/26S proteasome-mediated degradation of Top I (Top I down-regulation) and SUMO-1 (small ubiquitin-related modifier) conjugation to Top I. The roles of these two novel pathways in the repair/processing of Top I cleavable complexes are being investigated.

2. Studies on topoisomerase II-mediated DNA damage. Top II-mediated DNA damage has been recognized as an important form of DNA lesion. Top II performs its function through its delicate act of breaking/rejoining DNA strands to resolve topological problems arising during DNA replication. transcription. and chromosome condensation and segregation. Because of its delicate act on DNA. Top II is highly vulnerable to xenobiotics (e.g. VP-16 and doxorubicin). DNA structural modifications (e.g. abasic sites) and cellular stresses (e.g. pH and thiol stresses). These insults abort the Top II reaction by trapping the reversible covalent Top II-DNA intermediate. termed the cleavable complexes. We are currently investigating the role of Top II-mediated DNA damage in the following three areas; (1) the role of transcription elongation and the ubiquitin/26S proteasome pathway in repair/processing of Top II cleavage complexes. (2) the role of Top II isozymes in ischemic acidosis and the nuclear-mitochondial signaling pathway leading to acidotic apoptosis. and (3) the role of Top II isozymes in tumorigenesis.

3. Studies on telomere-initiated senescence and apoptosis. Telomeres have been suggested to play a role in cellular senescence/aging and tumorigenesis. Telomere de-protection is known to trigger DNA damage/apoptotic signaling and cellular senescence. We have recently demonstrated that introduction of telomeric G-quartet DNA into cells triggers DNA damage/apoptotic signaling and cellular senescence. Moreover. overexpression of TRF-2 suppresses the effect of G-quartet DNA. suggesting that G-quartet DNA may play a role in telomere regulation and cellular senescence. We are currently testing the hypothesis that the regulated inter-conversion between the G-quartet DNA and the single-stranded G-tail DNA plays a major regulatory role in telomere maintenance and cellular senescence/cell death.

Selected Publications

Desai SD, Wood LM, Tsai YC, Hsieh TS, Marks JR, Scott GL, Giovanella BC, Liu LF. (2008)
ISG15 as a novel tumor biomarker for drug sensitivity. Mol Cancer Ther. 7(6):1430-9.

Lin CP, Ban Y, Lyu YL, Desai SD, Liu LF. (2008) A ubiquitin-proteasome pathway for the repair of Top1-DNA covalent complexes. J Biol Chem. May 30. [Epub ahead of print]

Satyanarayana M, Rzuczek SG, Lavoie EJ, Pilch DS, Liu A, Liu LF, Rice JE. (2008) Ring-closing metathesis for the synthesis of a highly G-quadruplex selective macrocyclic hexaoxazole having enhanced cytotoxic potency. Bioorg Med Chem Lett. 18(13):3802-4.

Feng W, Satyanarayana M, Tsai YC, Liu AA, Liu LF, Lavoie EJ. (2008) Facile formation of hydrophilic derivatives of H-8,9-dimethoxy-5-[2-(N,N-dimethylamino)ethyl]-2,3-methylenedioxydibenzo[c,h] [1,6]naphthyridin-6-one (ARC-111) and its 12-aza analog via quaternary ammonium intermediates. Bioorg Med Chem Lett. 18(12):3570-2.

Fu X, Wan S, Lyu YL, Liu LF, Qi H. (2008) Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. PLoS ONE. 3(4):e2009.

Lyu YL, Kerrigan JE, Lin CP, Azarova AM, Tsai YC, Ban Y, Liu LF. (2007) Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 67(18):8839-46.

Azarova, A. M., Yi Lisa Lyu, Y. L., Lin, C.-P., Tsai,Y.-C., Lau, J. Y.-N., Wang, J. C. and Liu, L. F. (2007). Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci U S A. 104(26):11014-9.

Hars, E. S., Qi, H., Ryazanov, A. G., Jin, S., Cai, L., Hu, C. and Liu, L. F. (2007). Autophagy regulates aging in C. elgans. Autophagy 3:93-95.

Tsang, C. K., Qi, H., Liu, L. F. and Zheng, X. F. S. (2007). Targeting mammalian target of Rapamycin (mTOR) for health and diseases”. Drug Discovery Today 12:112-124.

Desai, S. D., J. Wood, L. J., Tao-Shih Hsieh, T.-S., Marks, J. R., Scott, G. L., Giovanella, B. C. Liu, L. F. ISG15 as a biomarker for tumor cell sensitivity/resistance to Topoisomerase I-Targeting drugs” submitted to Cancer Res.

Lyu, Y. L., Kerrigan, J. E., Lin, C.-P., Azarova, A., Tsai, Y.-C. and Liu, L. F. Topoisomerase IIb-mediated DNA double-strand breaks: Implications in Doxorubicin cardiotoxicity and prevention by Dexrazoxane” submitted to Cancer Res.

Tsai, Y.-C., Qi, H. and Liu, L. F.(2007). Protection of DNA Ends by Telomeric 3’ G-Tail Sequences” J. Biol. Chem. in press

Su TL. Lin YW. Chou TC. Zhang X. Bacherikov VA. Chen CH. Liu LF. Tsai TJ. (2006) Potent antitumor 9-Anilinoacridines and acridines bearing an alkylating N-Mustard residue on the acridine chromophore: Synthesis and biological activity. J Med Chem. 49(12):3710-3718.

Yang M. Hsu CT. Ting CY. Liu LF. Hwang J. (2006) Assembly of a polymeric chain of SUMO1 on human topoisomerase I in vitro. J Biol Chem. 281(12):8264-74.

Desai SD. Haas AL. Wood LM. Tsai YC. Pestka S. Rubin EH. Saleem A. Nur-E-Kamal A. Liu LF. (2006) Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway. Cancer Res. 66(2):921-8.

Zhu S. Ruchelman AL. Zhou N. Liu A. Liu LF. LaVoie EJ. (2006) 6-Substituted 6H-dibenzo[c,h][2,6]naphthyridin-5-ones: reversed lactam analogues of ARC-111 with potent topoisomerase I-targeting activity and cytotoxicity. Bioorg Med Chem. 14(9):3131-43.

Zhu S. Ruchelman AL. Zhou N. Liu AA. Liu LF. LaVoie EJ. (2005) Esters and amides of 2,3-dimethoxy-8,9-methylenedioxy-benzo[i]phenanthridine-12-carboxylic acid: potent cytotoxic and topoisomerase I-targeting agents. Bioorg Med Chem. 13(24):6782-94. Epub 2005 Sep 8.

Bacherikov VA. Chou TC. Dong HJ. Zhang X. Chen CH. Lin YW. Tsai TJ. Lee RZ. Liu LF. Su TL. (2005) Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: synthesis and biological activity. Bioorg Med Chem. 13(12):3993-4006.

Ruchelman. A. L.. Houghton. P. J.. Zhou. N.. Liu. A.. Liu. L. F.. and LaVoie. E. J. (2005)5-(2-aminoethyl)dibenzo[c,h]napthyridin-6-ones:variation of N-alkyl substituents modulates sensitivity to efflux transporters associated with multidrug resistance. J. Med. Chem. 48:792-804.

Daroui. P.. Desai. S. D.. Li. T.-K.. Liu. A. and Liu. L. F. (2004). Hydrogen peroxide induces topoisomerase I-mediated DNA damage and cell death. J. Biol. Chem. 279(15):14587-14594.

Ruchelman. A. L.. Singh. S. K.. Ray. A.. Wu. X.. Yang. J. M.. Zhou. N.. Liu. A.. and Liu. L. F.. LaVoie. E. J. (2004). 11H-Isoquino[4,3-c]cinnolin-12-ones; novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity. Bioorg Med Chem. 12:795-806

Ruchelman. A. L.. Kerrigan. J. E.. Li. T. K.. Zhou. N.. Liu. A.. Liu. L. F.. and LaVoie. E. J.(2004). Nitro and amino substitution within the A-ring of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: influence on topoisomerase I-targeting activity and cytotoxicity. Bioorg Med Chem. 12:3731-3742.

Nur-E-Kamal A. Gross SR. Pan Z. Balklava Z. Ma J. Liu LF. (2004). Nuclear translocation of cytochrome c during apoptosis. J. Biol. Chem. 279:24911-24914.

Rajendra. R.. Malegaonkar. D.. Pungaliya. P.. Marshall. H.. Rasheed. Z.. Brownell. J.. and Liu. L. F.. Lutzker. S.. Saleem. A.. and Rubin E. H. (2004). Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J. Biol. Chem. 279(35):36440-36444.

Makhey. D.. Li. D.. Zhao. B.. Sim. S.-P.. Li. T. K.. Liu. A.. Liu. L. F. and LaVoie. E. J. (2003) Substituted benzo[i]phenanthridines as mammalian topoisomerase-targeting agents. Bioorganic Med. Chem. 11:1809-1820.

Ruchelman. A. L.. Singh. S. K.. Ray. A.. Wu. X. H.. Yang. J.-M.. Li. T. K.. Liu. A.. Liu. L. F.. and LaVoie. E. J. (2003). 5H-Dibenzo[c,h]1,6-naphthyridin-6-ones: Novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity. Bioorganic Med. Chem. 11:2061-2073.

Yu. Y.. Singh. S. K.. Liu. A.. Li. T.-K.. Liu. L. F.. and LaVoie. E. J. (2003). Substituted Dibenzo[c,h]cinnolines: Topoisomerase I-targeting anticancer agents. Bioorganic Med. Chem. 11:1475-1491.

Li. D.. Zhao. B.. Sim S.-P.. Tsai-Kun Li. T.-K.. Liu. A.. Liu. L. F.. and LaVoie. E. J. (2003). 2,3-Dimethoxybenzo[i]phenanthridines: Topoisomerase I-targeting anticancer agents. Bioorganic Med. Chem. 11:521-528.

Nur-E-Kamal. A.. Li. T.-K.. Zhang. A. Qi. H.. Hars. E. and Liu. L. F. (2003). Single-stranded DNA induces ATM/p53-dependent DNA damage and apoptotic signals. J. Biol. Chem. 278:12475-12481.

Desai. S. D.. Zhang. H.. Rodriguez-Bauman. A.. Yang. J.-M.. Wu. X.. Gounder. M. K.. Rubin. E. H. and Liu. L. F. (2003). Transcription-dependent degradation of topoisomerase I-DNA covalent complexes. Mol. Cell. Biol. 23:2341-2350.

Xiao. H.. Mao. Y.. Desai. S. D.. Zhou. N.. Ting. C.-Y.. Hwang. J. and Liu. L. F. (2003). The topoisomerase IIb Circular Clamp arrests transcription and signals a 26S proteasome pathway. Proc. Natl. Acad. Sci. USA. 100:3239-3244.

Xiao. H.. Li. T.-K.. J.-M. Yang and Liu. L. F. (2003). Acidic pH induces topoisomerase II-mediated DNA damage. Proc. Natl. Acad. Sci. USA. 100: 5205-5210.

Liu. L. F. (2003). "Degradation of topoisomerase cleavable complexes". in DNA Topoisomerases in Cancer Therapy: Present and Future. Ed. Toshiwo Andoh. Kluwer Academic/Plenum Publishers. London UK. pp79-88.

Qi. H.. Li. T.-K.. Kuo. D.. Nur-E-Kamal. A. and Liu. L. F. (2003). Inactivation of Cdc13p triggers MEC1-dependent apoptotic signals in yeast. J. Biol. Chem. 278:15136-15141.

Zhou. N.. Xiao. H.. Nur-E-Kamal. A. and Liu. L. F. (2003). DNA damage-mediated apoptosis induced by selenium compounds. J. Biol. Chem. 278:29532-29537.

Singh. S. K.. Ruchelman. A. L.. Li. T. K.. Liu. A.. Liu. L. F.. and LaVoie. E. J. (2003). Nitro and amino substitution in the D-ring of 5-(2-dimethylaminoethyl)- 2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-ones: effect on topoisomerase-I targeting activity and cytotoxicity. J. Med. Chem. 46:2254-2257.

Li. D.. Zhao. B.. Sim. S. P.. Li. T. K.. Liu. A.. Liu. L. F.. and LaVoie. E. J. (2003). 8,9 -methylenedioxybenzo[i]phenanthridines: topoisomerase I-targeting activity and cytotoxicity. Bioorg. Med. Chem. 11:3795-3805.

Li. T.-K.. Desai. S. D.. Daroui. P.. Liu. A. A.. Eszter S. Hars. Ruchelman. A. L.. LaVoie. E. J. and Liu. L. F. (2003). Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug. Cancer Res. 63:8400-8407.

Kerrigan J. E.. Pilch. D.S.. Ruchelman. A.L.. Zhou. N. Liu. A.. Liu. L.. and LaVoie. E. J. (2003). 5H-8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h]naphthyridin-6-ones and related compounds as TOP1-Targeting agents: influence of structure on the ternary cleavable complex formation. Bioorg. Med. Chem. Lett. 13:3395-3399.

Ting. C. Y.. Hsu. C. T.. Hsu. H. T.. Su. J. S. Chen. T. Y.. Tarn. W. Y.. Kuo. Y. H.. Whang-Peng. J.. Liu. L. F.. and Hwang. J. (2003). Isodiospyrin as a novel human DNA topoisomerase I inhibitor. Biochem. Pharmacol. 66:1981-1991.