4β-[4′-(1-(Aryl)ureido)benzamide]podophyllotoxins as DNA topoisomerase I and IIα inhibitors and apoptosis inducing agents

Kamal, Ähmed; Suresh, Palaniswamy; Ramaiah, M. Janaki; Reddy, T. Srinivasa; Kapavarapu, Ravikumar; Rao, Bolla Narasimha; Imthiajali, Syed; Pushpavalli, S. N. C. V. L.; Shankaraiah, Nagula; Pal‐Bhadra, Manika

doi:10.1016/j.bmc.2013.06.033

Cited by 32 publications

(17 citation statements)

References 41 publications

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“…Lignan, a phytoestrogen derivative compound which widely exists in herbs, exhibits various physiological effects including the improvement of liver and cardiovascular function and the prevention of osteoporosis and cancers [ 14 ]. Lignans have also been found to be potent inhibitors of human DNA topoisomerase-I and II [ 15 – 17 ]. Austrobailignan-1, a natural lignin, isolated from the leaf of K .…”

Section: Introductionmentioning

confidence: 99%

The Topoisomerase 1 Inhibitor Austrobailignan-1 Isolated from Koelreuteria henryi Induces a G2/M-Phase Arrest and Cell Death Independently of p53 in Non-Small Cell Lung Cancer Cells

Huang

Yang

et al. 2015

PLoS ONE

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Koelreuteria henryi Dummer, an endemic plant of Taiwan, has been used as a folk medicine for the treatment of hepatitis, enteritis, cough, pharyngitis, allergy, hypertension, hyperlipidemia, and cancer. Austrobailignan-1, a natural lignan derivative isolated from Koelreuteria henryi Dummer, has anti-oxidative and anti-cancer properties. However, the effects of austrobailignan-1 on human cancer cells have not been studied yet. Here, we showed that austrobailignan-1 inhibited cell growth of human non-small cell lung cancer A549 and H1299 cell lines in both dose- and time-dependent manners, the IC50 value (48 h) of austrobailignan-1 were 41 and 22 nM, respectively. Data from flow cytometric analysis indicated that treatment with austrobailignan-1 for 24 h retarded the cell cycle at the G2/M phase. The molecular event of austrobailignan-1-mediated G2/M phase arrest was associated with the increase of p21Waf1/Cip1 and p27Kip1 expression, and decrease of Cdc25C expression. Moreover, treatment with 100 nM austrobailignan-1 for 48 h resulted in a pronounced release of cytochrome c followed by the activation of caspase-2, -3, and -9, and consequently induced apoptosis. These events were accompanied by the increase of PUMA and Bax, and the decrease of Mcl-1 and Bcl-2. Furthermore, our study also showed that austrobailignan-1 was a topoisomerase 1 inhibitor, as evidenced by a relaxation assay and induction of a DNA damage response signaling pathway, including ATM, and Chk1, Chk2, γH2AX phosphorylated activation. Overall, our results suggest that austrobailignan-1 is a novel DNA damaging agent and displays a topoisomerase I inhibitory activity, causes DNA strand breaks, and consequently induces DNA damage response signaling for cell cycle G2/M arrest and apoptosis in a p53 independent manner.

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Section: Introductionmentioning

confidence: 99%

The Topoisomerase 1 Inhibitor Austrobailignan-1 Isolated from Koelreuteria henryi Induces a G2/M-Phase Arrest and Cell Death Independently of p53 in Non-Small Cell Lung Cancer Cells

Huang

Yang

et al. 2015

PLoS ONE

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“…Clearly, these preliminary data further confirmed that compound 31 could induce apoptosis in PC‐3 cancer cells. In addition to the currently mentioned proteins, derivatives of PPT have also been reported to inhibit tumor cell proliferation or induce tumor cell death by regulating a series of other apoptosis‐related proteins such as DNA topoisomerase‐I, DNA topoisomerase‐II, DNA topoisomerase‐IIα, NF‐κB, ERK, JNK, P16, P21, P38, P51, and caspases (Kamal et al., , , , , ; Lin, Huang, Chen, Lee, & Huang, ; Liu et al., ; Zhang et al., , ). Therefore, more detailed mechanistic investigations on newly synthesized derivatives are also needed and our bioactive probe‐based cellular target identification of PPT via dansyl‐PPT ( 34 ) and biotin‐PPT ( 35 ) are currently ongoing and will be disclosed in due time.…”

Section: Resultsmentioning

confidence: 99%

Click chemistry‐based synthesis and cytotoxic activity evaluation of 4α‐triazole acetate podophyllotoxin derivatives

Hou

Zhang

Luo³

et al. 2018

Chem Biol Drug Des

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A series of novel 4α‐triazole acetate podophyllotoxin derivatives were synthesized via click chemistry. In vitro cytotoxic activity evaluation showed that most of the derivatives exhibited potent inhibitory activities against the tested cancer cell lines with low nanomolar IC50 values. Further studies demonstrated that compound 31 exhibited broad‐spectrum cytotoxic activities, effectively overcame drug‐resistance, and showed relatively weak cytotoxicity on non‐cancer cells. Preliminary mechanistic studies indicated that 31 might have action on microtubule, cause cell cycle arrest at G2/M phase, and induce apoptosis in human PC‐3 cancer cells.

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“…Recently, we have reported a series of podophyllotoxin congeners as potential inhibitors of topoisomerase and tubulin polymerization. [28][29][30] On the whole, these compounds was found to overcome the limitations of Etoposide, with superior pharmacological profiles, suggesting the prospect of further optimization through rational C4 modifications.…”

Section: Introductionmentioning

confidence: 96%

One-pot synthesis of podophyllotoxin–thiourea congeners by employing NH2SO3H/NaI: Anticancer activity, DNA topoisomerase-II inhibition, and apoptosis inducing agents

Shankaraiah

Kumar

Amula

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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4β-[4′-(1-(Aryl)ureido)benzamide]podophyllotoxins as DNA topoisomerase I and IIα inhibitors and apoptosis inducing agents

Cited by 32 publications

References 41 publications

The Topoisomerase 1 Inhibitor Austrobailignan-1 Isolated from Koelreuteria henryi Induces a G2/M-Phase Arrest and Cell Death Independently of p53 in Non-Small Cell Lung Cancer Cells

The Topoisomerase 1 Inhibitor Austrobailignan-1 Isolated from Koelreuteria henryi Induces a G2/M-Phase Arrest and Cell Death Independently of p53 in Non-Small Cell Lung Cancer Cells

Click chemistry‐based synthesis and cytotoxic activity evaluation of 4α‐triazole acetate podophyllotoxin derivatives

One-pot synthesis of podophyllotoxin–thiourea congeners by employing NH2SO3H/NaI: Anticancer activity, DNA topoisomerase-II inhibition, and apoptosis inducing agents

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