Intercalative pyrimido[4′,5′:4,5]thieno(2,3-b)quinolines induce apoptosis in leukemic cells: a comparative study of methoxy and morpholino substitution

Abstract

DNA intercalating molecules are promising anticancer agents. Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and affect major physiological functions. In the present study, we have characterized two molecules with the same chemical backbone but different side chains, namely 8-methoxy pyrimido[4',5':4,5]thieno (2,3-b)quinoline-4(3H)-one (MPTQ) and 4-morpholino pyrimido[4',5':4,5]thieno(2,3-b)quinoline (morpho-PTQ) at the 8th and 4th position, respectively. Although both MPTQ and morpho-PTQ show similar biophysical properties with high DNA affinity, here we show that they differ in their biological activities. We find that MPTQ is many fold more potent than morpho-PTQ and is cytotoxic against different leukemic cell lines. IC(50) value of methoxy PTQ was estimated between 2-15 µM among the leukemic cells studied, while it was more than 200 µM when morpho-PTQ was used. Cell cycle analysis shows an increase in sub-G1 phase, without any particular cell cycle arrest. Annexin V staining in conjunction with comet assay and DNA fragmentation suggest that MPTQ induces cytotoxicity by activating apoptosis. Thus the observed low IC(50) value of MPTQ makes it a promising cancer chemotherapeutic agent.

A Novel Anticancer Agent, 8-Methoxypyrimido[4′,5′:4,5]thieno(2,3-b) Quinoline-4(3H)-One Induces Neuro 2a Neuroblastoma Cell Death through p53-Dependent, Caspase-Dependent and -Independent Apoptotic Pathways

“…Our results also suggested that, anticancer effect of MPTQ on neuroblastoma cells continued over a long period of time. A similar result was also observed in MPTQ treated various leukemic cells [20]. We have not tested the unwanted toxic side effects of MPTQ.…”

“…Here we found that, MPTQ treatment induces DNA double strand breaks of nucleosome-sized fragments in a dose-dependent manner. Nuclear DNA fragmentation was also reported in MPTQ-treated leukemic cells [20]. Thus, our results for the first time indicated that MPTQ-mediated neuroblastoma cell death might be activating and employing cellular apoptotic machineries.…”

“…Furthermore, our results for the first time illustrated the mechanisms associated with MPTQ-mediated cytotoxicity in neuroblastoma cells. Although the reports on anticancer property of MPTQ has been very limited, but MPTQ inhibited proliferation of various leukemic cells [20], [21], melanoma cell [19] and mouse breast carcinoma cells [21]. Till today, a single report suggests the cytotoxic effect of MPTQ on neuro 2a neuroblastoma cell with approximately 40% growth inhibition after 48 hrs [19].…”

“…One such compound, 8-methoxypyrimido[4′,5′:4,5]-thieno(2,3-b)quinoline-4(3H)-one (MPTQ), containing tetracyclic condensed quinoline ring system was developed [17] and was shown to intercalate with calf thymus DNA [18]. MPTQ has been shown to exhibit its cytotoxic effect on human promyelocytic leukemia HL-60, melanoma B16F10 cells [19] and induces apoptosis in a wide range of leukemic cell lines [20], [21]. Mechanisms related to MPTQ-mediated cancer cell death are limited.…”

Enhanced Efficacy of Pluronic Copolymer Micelle Encapsulated SCR7 against Cancer Cell Proliferation

“…Following treatment with encapsulated form of SCR7 (0, 0.1, 0.2 and 0.5 mg · ml −1 ) for 48 h, cells were harvested, washed and stained with Annexin‐FITC for 1 h. Cells were stained with PI for 15 min, washed and suspended in 1× PBS. Cells were acquired by BD FACS verse and plotted density plot with the help of WinMDI as described earlier …”