A novel DNA intercalator, butylamino-pyrimido[4',5':4,5]selenolo(2,3-b)quinoline, induces cell cycle arrest and apoptosis in leukemic cells.
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.
Shahabuddin
M S
MS
Department of Biochemistry, Indian Institute of Science, Bangalore, 560 012, India.
Nambiar
Mridula
M
Choudhary
Bibha
B
Advirao
Gopal M
GM
Raghavan
Sathees C
SC
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology*; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D007364:Intercalating Agents; D016566:Organoselenium Compounds; D010718:Phosphatidylserines; D011804:Quinolines; C547916:butylamino-pyrimido(4',5'-4,5)selenolo(2,3-b)quinoline; D004247:DNA; C037219:quinoline