Phenazine-1-carboxamide (PCN) from Pseudomonas sp. strain PUP6 selectively induced apoptosis in lung (A549) and breast (MDA MB-231) cancer cells by inhibition of antiapoptotic Bcl-2 family proteins
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Phenazine-1-carboxamide (PCN), a naturally occurring simple phenazine derivative isolated from Pseudomonas sp. strain PUP6, exhibited selective cytotoxic activity against lung (A549) and breast (MDA-MB-231) cancer cell lines in differential and dose-dependent manner compared to normal peripheral blood mononuclear cells. PCN-treated cancer cells showed the induction of apoptosis as evidenced by the release of low level of LDH, morphological characteristics, production of reactive oxygen species, loss of mitochondrial membrane potential (ΔΨm) and induction of caspase-3. At molecular level, PCN instigates apoptosis by mitochondrial intrinsic apoptotic pathway via the overexpression of p53, Bax, cytochrome C release and activation of caspase-3 with the inhibition of oncogenic anti-apoptotic proteins such as PARP and Bcl-2 family proteins (Bcl-2, Bcl-w and Bcl-xL). The in silico docking studies of PCN targeted against the anti-apoptotic members of Bcl-2 family proteins revealed the interaction of PCN with the BH3 domain, which might lead to the induction of apoptosis due to the inhibition of antiapoptotic proteins. Due to its innate inhibition potential of antiapoptotic Bcl-2 family proteins, PCN may be used as potent anticancer agent against both lung and breast cancer.
KeywordsPhenazine-1-carboxamide Cytotoxic p53 Bcl-2 family proteins Caspase-3
The financial support from the Ministry of Science and Technology and Department of Biotechnology-Boost to University Interdisciplinary Life science Departments for Education and Research (DBT-BUILDER) programme, New Delhi, Government of India is gratefully acknowledged.
Conflict of interest
The authors declare that they have no conflict of interest.
- 11.Cimmino A, Andolfi A, Evidente A (2013) Microbion phenazines. In: Chincholkar, Thomashow (eds) Phenazine as an anticancer agent. Springer, Heidelberg, pp 217–243Google Scholar
- 19.Kornblau SM, Qiu YH, Bekele BN, Cade JS, Zhou X, Harris D, Andreeff M (2006) Studying the right cell in acute myelogenous leukemia: dynamic changes of apoptosis and signal transduction pathway protein expression in chemotherapy resistant ex vivo selected “survivor cells”. Cell Cycle 5:2769–2777CrossRefPubMedGoogle Scholar
- 22.Chan FK, Moriwaki K, De Rosa MJ (2013) Detection of necrosis by release of lactate dehydrogenase (LDH) activity. Methods Mol Biol 979:6–70Google Scholar
- 23.Zilla MK, Nayak D, Amin H, Nalli Yedukondalu N, Kitchlu S, Goswami A, Ali A (2014) 4′-Demethyl-deoxypodophyllotoxin glucoside isolated from Podophyllum hexandrum exhibits potential anticancer activities by altering Chk-2 signaling pathway in MCF-7 breast cancer cells. Chem Biol Interact. doi: 10.1016/j.cbi.2014.09.022 PubMedGoogle Scholar
- 25.Shanmugaraj S, Selvaraj S, Murugan VP, Rajaganapathy BR, Shanmuganathan MV, Devaraj NS, Subhadra LB (2010) 3β-Hydroxylup-20(29)-ene-27,28-dioic acid dimethyl ester, a novel natural product from Plumbago zeylanica inhibits the proliferation and migration of MDA MB-231 cells. Chem Biol Interact 188:412–420CrossRefGoogle Scholar
- 26.Chin-A-Woeng TFC, Bloemberg GV, Van der Bij AJ, Van der Drift KMGM, Schripse-ma J, Kroon B, Scheffer RJ, Keel C, Bakker PAHM, Tichy H, de Bruijn FJ, Thomas-Oates JE, Lugtenberg BJJ (1998) Biocontrol by phenazine-1-carboxamide producing Pseudomonas chlororaphis PCL1391 of tomato root rot caused by Fusarium oxysporum f. sp. radicis-lycopersici. Mol Plant Microbe Interact 11:1069–1077CrossRefGoogle Scholar
- 28.Balachandran C, Sangeetha B, Duraipandiyan V, Raj MK, Ignacimuthu S, Al-Dhabi NA, Balakrishna K, Parthasarathy K, Arulmozhi NM, Arasu MV (2014) A flavonoid isolated from Streptomyces sp. (ERINLG-4) induces apoptosis in human lung cancer A549 cells through p53 and cytochrome c release caspase dependant pathway. Chem Biol Interact. doi: 10.1016/j.cbi.2014.09.019 PubMedGoogle Scholar