The broad success of Pt(ll) based drugs in human cancer chemotherapy, has led to interest in the potential for another transition metal, Ru (II), as an antineoplastic agent [3]. A number of DMA-binding, cationic dinuclear Ru(ll) polypyridyl complexes have been prepared in racemic form, and preliminary studies in cultured malignant cell lines as well as in isogenic, orthotopic mouse melanoma model show promising antineoplastic activity. It is hypothesized that some of these Ru(ll) complexes can be developed into effective anticancer agents, and that the antitumor activity of Ru(ll) complexes can be predicted on the basis of specific, tunable structural features. We propose to test our hypothesis in studies with these three specific aims: 1. Defining the antineoplastic activity of Ru(ll) complexes in cultured human malignant cells as well as with epithelial cells. These studies will address the hypothesis that some of these Ru(ll) complexes will exhibit antineoplastic activity against an array of histological types of human cancers. 2. Determining the structure-toxicity relationships for Ru(ll) complexes. These studies will address the hypothesis that analogs with 17 A bridges will not be acutely toxic to mice whereas those with the 12 A bridges will be toxic. They will also address the hypothesis that the absolute chirality of the complex can affect the level of toxicity because of the differing ability of the two enantiomers to inhibit acetylcholinesterase activity. 3. Determining the structure-activity relationships for Ru(ll) complexes. These studies will address the hypothesis that the complexes with long, redox-active bridging ligands will be superior to the shorter, non- redox active bridges for intercalation, redox activity, and anti-tumor activity. These studies will also address the hypothesis that optically resolved (enantiopure) complexes will exhibit different DNA binding abilities and therefore exhibit different antineoplastic activity. The use of transition metals, in particular Pt(ll), in human chemotherapy has led to dramatic improvements in the prognosis for a great many cancer patients. Another metal, Ru(ll), has similar properties and is being explored for its potential in chemotherapy. Preliminary results are promising. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15CA113747-01A1
Application #
7072026
Study Section
Special Emphasis Panel (ZRG1-F09-S (20))
Program Officer
Misra, Raj N
Project Start
2006-04-01
Project End
2009-08-28
Budget Start
2006-04-01
Budget End
2009-08-28
Support Year
1
Fiscal Year
2006
Total Cost
$222,000
Indirect Cost
Name
University of Texas Arlington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
064234610
City
Arlington
State
TX
Country
United States
Zip Code
76019
Shu, Yang; Breitbach, Zachary S; Dissanayake, Milan K et al. (2015) Enantiomeric separations of ruthenium (II) polypyridyl complexes using HPLC with cyclofructan chiral stationary phases. Chirality 27:64-70
Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I et al. (2014) Histone methyltransferase EZH2 is transcriptionally induced by estradiol as well as estrogenic endocrine disruptors bisphenol-A and diethylstilbestrol. J Mol Biol 426:3426-41
Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I et al. (2014) Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo. J Steroid Biochem Mol Biol 141:160-70
Kasiri, Sahba; Ansari, Khairul I; Hussain, Imran et al. (2013) Antisense oligonucleotide mediated knockdown of HOXC13 affects cell growth and induces apoptosis in tumor cells and over expression of HOXC13 induces 3D-colony formation. RSC Adv 3:3260-3269
Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I et al. (2013) Antisense transcript long noncoding RNA (lncRNA) HOTAIR is transcriptionally induced by estradiol. J Mol Biol 425:3707-22
Ansari, K I; Kasiri, S; Mandal, S S (2013) Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo. Oncogene 32:3359-70
Yadav, Abhishek; Janaratne, Thamara; Krishnan, Arthi et al. (2013) Regression of lung cancer by hypoxia-sensitizing ruthenium polypyridyl complexes. Mol Cancer Ther 12:643-53
Ansari, K I; Kasiri, S; Mishra, B P et al. (2012) Mixed lineage leukaemia-4 regulates cell-cycle progression and cell viability and its depletion suppresses growth of xenografted tumour in vivo. Br J Cancer 107:315-24
Shrestha, Bishakha; Ansari, Khairul I; Bhan, Arunoday et al. (2012) Homeodomain-containing protein HOXB9 regulates expression of growth and angiogenic factors, facilitates tumor growth in vitro and is overexpressed in breast cancer tissue. FEBS J 279:3715-3726
Ansari, Khairul I; Hussain, Imran; Kasiri, Sahba et al. (2012) HOXC10 is overexpressed in breast cancer and transcriptionally regulated by estrogen via involvement of histone methylases MLL3 and MLL4. J Mol Endocrinol 48:61-75

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