Non-small cell lung cancer (NSCLC) is the most prevalent type of
lung cancer. However, there has been little improvement in its cure rate in the last 30 years, due to its intricate heterogeneity and drug resistance. Accumulating evidences have demonstrated that dysregulation of
calcium (Ca2+) homeostasis contributes to
oncogenesis and promotes
tumor development. Inhibitors of Ca2+ channels/transporters to restore intracellular Ca2+ level were found to arrest
tumor cell division, induce apoptosis, and suppress
tumor growth both in vitro and in vivo.
Dolutegravir (DTG), which is a first-line drug for
Acquired Immune Deficiency Syndrome (
AIDs) treatment, has been shown to increase intracellular Ca2+ levels and
Reactive oxygen species (ROS) levels in human erythrocytes, leading to suicidal erythrocyte death or eryptosis. To explore the potential of DTG as an
antitumor agent, we have designed and synthesized a panel of compounds based on the principle of biologically active substructure splicing of DTG. Our data demonstrated that 7-methoxy-4-methyl-6,8-dioxo-N-(3-(1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (DTHP), a novel derivative of DTG, strongly inhibited the colony-forming ability and proliferation of NSCLC cells, but displayed no cytotoxicity to normal lung cells. DTHP treatment also induced apoptosis and upregulate intracellular Ca2+ level in NSCLC cells significantly. Inhibiting Ca2+ signaling alleviated DTHP-induced apoptosis, suggesting the perturbation of intracellular Ca2+ is responsible for DTHP-induced apoptosis. We further discovered that DTHP activates AMPK signaling pathway through binding to SERCA, a Ca2+-
ATPase. On the other hand, DTHP treatment promoted mitochondrial ROS production, causing
mitochondrial dysfunction and cell death. Finally, DTHP effectively inhibited
tumor growth in the mouse xenograft model of
lung cancer with low toxicity to normal organs. Taken together, our work identified DTHP as a superior
antitumor agent, which will provide a novel strategy for the treatment of NSCLC with potential clinical application.