N-(2-hydroxyphenyl)-2-phenazinamine from Nocardiopsis exhalans induces p53-mediated intrinsic apoptosis signaling in lung cancer cell lines

For the past two decades, the deaths caused by cancer have reduced by 26% resulting in an overall decrease in cancer deaths by 2.4 million [1]; however, lung cancer continues as one of the leading causes of cancer-related mortalities, with a projected 2.1 million deaths (21%) [2]. Lung cancer is classified as non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and lung carcinoid tumor and NSCLC is the most common type of lung cancer which covers 85% of lung cancers [3]. Among the basic treatments for NSCLC including surgery, radiation therapy, targeted therapy and immune therapy, chemotherapy is considered cost effective and toxic to healthy cells. Researchers are focusing on the development of drugs that specifically targeting the p53 mediated intrinsic apoptosis signaling pathways which is consistent to develop novel treatment strategies as they are the core of disease progression [4].

Destruction of permanent cancer cells is a key point for efficient cancer therapy. But the role of p53 in tumor suppression and proliferation is still not completely understood. However, the protection of apoptosis and aging functions of p53 would be most useful for cancer therapy [5]. p53, a key apoptotic marker protein significantly regulates the initiation of intrinsic and extrinsic apoptosis pathways and controls the cell protection or cell destruction function upon several cellular stresses [6]. In response to severe genotoxic stress, p53 strongly activates the cell destruction through apoptosis, and for mild DNA damage, p53 induces damage repair and survival for cell protection [7]. Through transcriptional changes of phosphorylation, subcellular localization and interaction with oncogenes, p53 gets involved in induction, stimulation and control of the apoptotic genes including Bax, PUMA, NOXA, and p21 by transcription [8]. Recently the researchers are focusing on the naturally derived bioactive compounds to activate the p53 mediated apoptosis for better treatment of cancer.

Marine organisms, especially marine actinomycetes, have a significant contribution in the development of novel drugs to combat against cancer and associated diseases [9]. In continuation of our previous studies [[10], [11], [12]], we have isolated the bioactive compound N-(2-hydroxyphenyl)-2-phenazinamine (NHP) from marine actinomycetes Nocardiopsis exhalans [13]. Interestingly, the NHP bears the core moiety in similarity with 2-methylphenazine [14], 2-hydroxyphenazine [15], and phenazin-2-amine [16] (Fig. 1) which have excellent biomedical applications including anticancer properties. Hence, the present study aims to assess the anticancer activity of NHP and various fluorescent-based staining assays are employed to determine the apoptotic effect of NHP in lung cancer. Further, the RT-PCR and western blotting techniques are used to determine the underlying mechanism of action of NHP for their potential anticancer activity.

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