NDLI: Investigation of the mechanism and apoptotic pathway induced by 4β cinnamido linked podophyllotoxins against human lung cancer cells A549

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Investigation of the mechanism and apoptotic pathway induced by 4β cinnamido linked podophyllotoxins against human lung cancer cells A549

Content Provider	Springer Nature Link
Author	Kamal, Ahmed Nayak, V. Lakshma Bagul, Chandrakant Vishnuvardhan, M. V. P. S. Mallareddy, Adla
Copyright Year	2015
Abstract	Apoptosis is essential for normal development and the maintenance of homeostasis. It plays a necessary role to protect against carcinogenesis by eliminating damaged cells. Many studies have demonstrated that the dysregulation of apoptosis results in cancer and this provides an approach to develop therapeutic agents via inducing apoptosis. In our previous studies 4β-cinnamido linked podophyllotoxin conjugates were synthesized and evaluated for their cytotoxic activity in a panel of five human cancer cell lines and the new molecules like 17a and 17f were considered as potential leads. The cytotoxic activity was comparable to etoposide. These observations prompted us to investigate the mechanism underplaying the cytotoxic activity and apoptotic pathway induced by these compounds in human lung cancer cells A459. The results of the present study revealed that these compounds exhibited DNA topoisomerase IIα inhibition and induced mitochondrial mediated apoptosis. It was further confirmed by Mitochondrial membrane potential, Cytochrome c release, cleavage of poly (ADP-ribose) polymerase (PARP), Reactive oxygen species (ROS) generation, regulation of antiapoptotic protein Bcl-2 and pro apoptotic protein Bax studied by Western blot analysis. Annexin V-FITC assay also suggested that these compounds induced cell death by apoptosis. Pretreatment with N-acetyl-l-cysteine (NAC) prevented the generation of ROS. Further, pretreatment with NAC significantly inhibited 17a and 17f induced apoptosis, suggesting that ROS are the key mediators for 17a and 17f induced apoptosis. These data indicate that these compounds might induce apoptosis in A549 cells through a ROS mediated mitochondrial dysfunction pathway. Moreover, these compounds did not significantly inhibit the noncancerous human embryonic kidney cells, HEK-293. Docking studies also elucidate the potential of these molecules to bind to the DNA topoisomerase II.Podophyllotoxin analogs were investigated for their mechanism and apoptotic pathway against lung cancer cell line, A549. These podophyllotoxin analogs inhibited DNA topoisomerase IIα and induced mitochondrial mediated apoptosis in lung cancer cell line, A549. Western blot analysis suggested that these compounds inhibited the DNA topoisomerase IIα. Studies like, Measurement of mitochondrial membrane potential (∆Ψm), Generation of intracellular reactive oxygen species (ROS) and Annexin V-FITC assay suggested that these compounds induced mitochondrial mediated apoptosis. Pretreatment with N-acetyl-l-cysteine (NAC) suggested that ROS plays a role in 17a and 17f induced apoptosis. Further the apoptotic effect of these compounds was confirmed by western blot analysis of pro apoptotic protein Bax and antiapoptotic protein Bcl-2, Cytochrome c release and cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, these compounds did not significantly inhibit the noncancerous human embryonic kidney cells, HEK-293.
Starting Page	1518
Ending Page	1529
Page Count	12
File Format	PDF
ISSN	13608185
Journal	Apoptosis
Volume Number	20
Issue Number	11
e-ISSN	1573675X
Language	English
Publisher	Springer US
Publisher Date	2015-09-19
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Anticancer activity Topoisomerase IIα and IIβ Western blot analysis Annexin V-FITC Apoptosis Cancer Research Cell Biology Oncology Biochemistry Virology
Content Type	Text
Resource Type	Article
Subject	Pharmaceutical Science Biochemistry (medical) Cell Biology Clinical Biochemistry Cancer Research Pharmacology

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