Abstract
Temozolomide-perillyl alcohol conjugate (TMZ − POH), a novel temozolomide analog, was reported to play a cytotoxic role in triple-negative breast cancer and TMZ-resistant gliomas. In a current study we had demonstrated how TMZ − POH also exhibited its cytotoxicity against non-small cell lung cancer (NSCLC), the most common type of lung cancer, as evidence from cell/tumor proliferation inhibition, G2/M arrest, DNA damage and mitochondrial apoptosis. Importantly, TMZ − POH’s cytotoxicity is closely related to reactive oxygen species (ROS) accumulation because it can be reversed by two ROS scavengers, catalase (CAT) and N-acetyl-L-cysteine (NAC). TMZ − POH induces mitochondrial transmembrane potential (MTP) decrease and ROS accumulation, in turn activates mitogen-activated protein kinase (MAPKs) signaling and mitochondrial apoptosis, and then exerts its cytotoxicity, thus proposing TMZ − POH as a potential therapeutic candidate for NSCLC.
Highlights
Recent studies have demonstrated that perillyl alcohol (POH), a naturally occurring monoterpene which exerts promising antitumor activity in a variety of cancers including breast[12], pancreas[13], and lung carcinomas[14], has the amazing capability to enhance the cytotoxicity of TMZ in several tumors including TMZ-resistant gliomas[15]
We have demonstrated the cytotoxic effect of TMZ − POH on non-small cell lung cancer (NSCLC)
Our data showed TMZ and TMZ + POH seemed to play a modest role in G2/M arrest, apoptosis and DNA damage in H520 but not in A549 cells
Summary
Recent studies have demonstrated that perillyl alcohol (POH), a naturally occurring monoterpene which exerts promising antitumor activity in a variety of cancers including breast[12], pancreas[13], and lung carcinomas[14], has the amazing capability to enhance the cytotoxicity of TMZ in several tumors including TMZ-resistant gliomas[15]. We have demonstrated that TMZ − POH exhibits anti-tumor activities against NSCLC more strongly than its individual constituents or their combination in vitro and in vivo. As excessive levels of ROS stress can be toxic to the cells, cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents[23]. The overall hypothesis of the present study is that TMZ − POH-induced ROS is the key contributor to its anti-tumor activities, which triggers cell cycle-dependent DNA damage and G2/M arrest as well as downstream signal activation, and cell death, proposing TMZ − POH as a potential therapeutic candidate for NSCLC
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