A novel DNA intercalator, butylamino-pyrimido[4′,5′:4,5]selenolo(2,3-b)quinoline, induces cell cycle arrest and apoptosis in leukemic cells
- 270 Downloads
DNA intercalators are one of the most commonly used chemotherapeutic agents. Novel intercalating compounds of pyrimido[4′,5′:4,5]selenolo(2,3-b)quinoline series having a butylamino or piperazino group at fourth position (BPSQ and PPSQ, respectively) are studied. Our results showed that BPSQ induced cytotoxicity whereas PPSQ was cytostatic. The cytotoxicity induced by BPSQ was concentration- and time-dependent. Cell cycle analysis and tritiated thymidine assay revealed that BPSQ affects the cell cycle progression by arresting at S phase. The absence of p-histone H3 and reduction in the levels of PCNA in the cells treated with BPSQ further confirmed the cell cycle arrest. Further, annexin V staining, DNA fragmentation, nuclear condensation and changes in the expression levels of BCL2/BAD confirmed the activation of apoptosis. Activation of caspase 8 and lack of cleavage of caspase 9, caspase 3 and PARP suggest the possibility of BPSQ triggering extrinsic pathway for induction of apoptosis, which is discussed. Hence, we have identified a novel compound which would have clinical relevance in cancer chemotherapeutics.
KeywordsChemotherapy Double-strand breaks Cytotoxicity DNA damage Anticancer drug
We thank Prof. Ambeker SY and members of the SCR laboratory for discussions and help. This work was supported by Lady Tata Memorial Trust international award for leukemia research, London; grants from DBT, India (BT/PRS129/GBD/27/7/2006), and IISc start up grant for SCR. We also thank Dr. Raghavan Varadarajan for financial assistance. SMS is supported by DBT postdoctoral fellowship from DBT, India. MN is supported by senior research fellowship from CSIR, India.
Conflict of interest statement
Authors disclose that there is no conflict of interest.
- 1.Kirsch IR (1993) The causes and consequences of chromosomal translocations. CRC, Boca RatonGoogle Scholar
- 14.Baguley BC (1991) DNA intercalating anti-tumor agents. Anticancer Drugs 6:1–35Google Scholar
- 16.Tilak Raj T, Ambeker SY (1988) Synthesis of pyrimido[4′,5′:4,5]thieno(2,3-b)quinoline-4(3H)-ones. J Chem Res 50:537–551Google Scholar
- 17.Nandeeshaiah SK, Ambekar SY (1998) Synthesis, Dimroth rearrangment and blood platelet disaggregation property of pyrimido[4′,5′:4,5]selenolo(2,3-b)quinolines: a new class of condensed quinoline. Indian J Chem 37:995–1000Google Scholar
- 18.Nandeeshaiah SK, Ambeker SY (1994) Synthesis of 2-aryl-1,2,3,4-tetrahydropyrido [2′,3′:4,5] thieno[2,3-b]quinolin-4-ones. Indian J Chem 33:375–379Google Scholar
- 23.Shahabuddin MS, Gopal M, Raghavan SC (2007) Intercalating and antitumour activity of 4-oxopyrimido[4′,5′:4,5]thieno(2,3-b)quinoline-4(3H)-one. J Cancer Mol 3(5):139–146Google Scholar
- 24.Shahabuddin MS, Gopal M, Raghavan SC (2008) Intercalating, cytotoxic, antitumour activity of 8-Chloro and 4-Morpholinopyrimido [4′,5′:4,5]thieno(2,3-b)quinolines. J Photochem Photobiol 94:13–19Google Scholar
- 32.Takefumi K et al (2003) Ritterazine B, a new cytotoxic narural compound, induces apoptosis in cancer cells. Cancer Chemother Pharmacol 51:202–208Google Scholar
- 44.Cattaneo-Pangrazzi RM et al (2000) Cell-cycle arrest and p53-independent induction of apoptosis in vitro by the new anticancer drugs 5-FdUrd-P-FdCydOct and dCydPam-P-FdUrd in DU-145 human prostate cancer cells. J Cancer Res Clin Oncol 126(5):247–256. doi: 10.1007/s004320050339 CrossRefPubMedGoogle Scholar