Abstract
Non-small cell lung carcinoma (NSCLC) is a major killer in cancer related human death. Its therapeutic intervention requires superior efficient molecule(s) as it often becomes resistant to present chemotherapy options. Here we report that vapor of volatile oil compounds obtained from Litsea cubeba seeds killed human NSCLC cells, A549, through the induction of apoptosis and cell cycle arrest. Vapor generated from the combined oils (VCO) deactivated Akt, a key player in cancer cell survival and proliferation. Interestingly VCO dephosphorylated Akt at both Ser473 and Thr308; through the suppression of mTOR and pPDK1 respectively. As a consequence of this, diminished phosphorylation of Bad occurred along with the decreased Bcl-xL expression. This subsequently enhanced Bax levels permitting the release of mitochondrial cytochrome c into the cytosol which concomitantly activated caspase 9 and caspase 3 resulting apoptotic cell death. Impairment of Akt activation by VCO also deactivated Mdm2 that effected overexpression of p53 which in turn upregulated p21 expression. This causes enhanced p21 binding to cyclin D1 that halted G1 to S phase progression. Taken together, VCO produces two prong effects on lung cancer cells, it induces apoptosis and blocked cancer cell proliferation, both occurred due to the deactivation of Akt. In addition, it has another crucial advantage: VCO could be directly delivered to lung cancer tissue through inhalation.
Highlights
Lung cancer is one of the most prevalent cancers and a major cause of worldwide cancer related death in approximately 1.4 million patients each year [1]
The primary antibodies for Phosphorylated Akt (pAkt) (Thr308; sc-135650), pAkt1/2/3 (Ser473; sc-7985-R), Akt 1/2/3, pPDK1 (Ser241; sc-101775), Bcl-xL, pBad (Ser136; sc-7999), Bad, pMdm2 (Ser166; sc293105), p53, p21, cyclin D1, poly[ADP-ribosyl]-polymerase (PARP), Cytochrome c and b-actin were purchased from Santa Cruz Biotechnology Inc., California, USA and mTOR (#2983) was procured from Cell Signaling Technology Inc., Danvers, MA, USA
Bioactivity guided isolation and purification of oils from the seed of Litsea cubeba The extracted crude oil vapor from Litsea cubeba seeds was examined for anti-cancer activity in A549 lung cancer cells
Summary
Lung cancer is one of the most prevalent cancers and a major cause of worldwide cancer related death in approximately 1.4 million patients each year [1]. Chemotherapy and/or irradiation usually fails because NSCLC cells are intrinsically resistant to such therapies, prognosis of NSCLC is notably poor [3,4]. All these affected a very limited therapeutic choice for lung cancer. In NSCLC cells, Akt/PKB is the constitutively active kinase which promotes cellular survival [5]. Activation of Akt occurs when it is recruited into the cell membrane through its PH domain and phosphorylated at Thr308 and Ser473 through the mediation of PDK1 (phosphoinositide dependent kinase 1) and mTOR (mammalian target of rapamycin) respectively [6,7]. Apoptotic response due to the inhibition of Akt has been observed at varying degrees in several types of cancers [10,11] it could be crucial in lung cancer because enhanced phosphorylated form of Akt occurs perpetually [12]
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