MOLECULAR CARCINOGENESIS A Novel DNA Intercalator, 8-Methoxy Pyrimido[4 0 ,5 0 :4,5]Thieno (2,3-b)Quinoline-4(3H)- One Induces Apoptosis in Cancer Cells, Inhibits the Tumor Progression and Enhances Lifespan in Mice With Tumor Sheetal Sharma, 1 Kuppusamy Panjamurthy, 1 Bibha Choudhary, 1,2 Mrinal Srivastava, 1 MS Shahabuddin, 1 Ranjit Giri, 3 Gopal M. Advirao, 4 and Sathees C. Raghavan 1 * 1 Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, India 2 Institute of Bioinformatics and Applied Biotechnology, Biotech Park, Electronics City, Bangalore, Karnataka, India 3 National Brain Research Center, Manesar, Gurgaon, Haryana, India 4 Department of Biochemistry, Kuvempu University, Davanagere, Karnataka, India Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and interfere with physiologi- cal functions. In the present study, we evaluate the chemotherapeutic potential of MPTQ on animal models and its mode of action. In order to test the antitumor activity, monohydrochloride of MPTQ was orally administered in mice bearing tumor. Results showed a significant inhibition of tumor growth compared to that of untreated controls. More importantly, mean lifespan of tumor bearing animals treated with MPTQ was significantly higher as compared to that of untreated tumor bearing mice suggesting that the treatment affected viability of cancerous cells, but not of normal cells. Consistent with this, we find that administration of MPTQ to normal mice did not cause any major side effects as observed upon hematological and serum profiling. We also found that MPTQ induces cytotoxicity in cancer cell lines, by activating apoptosis both by intrinsic and extrinsic pathways. Thus, MPTQ could be used as a potential cancer therapeutic agent. ß 2011 Wiley Periodicals, Inc. Key words: chemotherapy; DNA intercalator; double-strand breaks; extrinsic pathway of apoptosis; DNA damage; anticancer drug INTRODUCTION DNA, the genetic material of an organism, con- trols cellular functions and has been a target for treatment of cancer. DNA intercalators are a class of cancer therapeutic agents, which can intercalate between specific sequences [1]. Although biophysi- cal studies such as CD, UV-fluorescence, differen- tial scanning calorimetry etc. help in deciphering the binding of these molecules, cytological techni- ques are important to prove their physiological importance. Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and affect major physiological functions. Pyrimidothienoqui- nolines, a new class of structural analogues of ellip- ticine, have been described as novel and rational intercalating ligands with potential antitumor ac- tivity [2]. However, many intercalators currently used are highly toxic to normal cells and therefore, design and synthesis of novel molecules that do not affect the normal cellular physiology are of prime importance. Quinolines are one of the DNA intercalators, which have been extensively studied for their DNA binding properties. Sandramycin is a naturally oc- curring quinoline having an anti-tumorigenic ac- tivity [2,3]. DNA binding properties of many derivatives of quinolines, after addition of side chains containing various functional groups were studied [4,5]. A binding affinity of 10 4 –10 6 M 1 to DNA has been shown for pyrimidothieno/selenolo quinolines with methoxy, morpholino, diethyla- mino, propylamino, oxochloro, anilino, butyla- mino, or piperazino substitutions showing that Additional Supporting Information may be found in the online version of this article. Abbreviations: EAC, Ehrlich ascites carcinoma; ROS, reactive oxy- gen species; PI, propidium iodide; DLA, Dalton’s lymphoma; ALP, alkaline phosphatase; IHC, immunohistochemistry. Sheetal Sharma and Kuppusamy Panjamurthy contributed equal- ly to the work. Authors declare that there is no competing interest. *Correspondence to: Department of Biochemistry, Indian Insti- tute of Science, Bangalore 560 012, Karnataka, India. Received 10 May 2011; Revised 2 December 2011; Accepted 6 December 2011 DOI 10.1002/mc.21867 Published online in Wiley Online Library (wileyonlinelibrary.com). ß 2011 WILEY PERIODICALS, INC.