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Many clinically approved anticancer agents target DNA.(1–4) These DNA-targeting agents can be classified as alkylating agents, antimetabolites, topoisomerase inhibitors, or radiomimetics.(1,5) Topoisomerases are essential for the modification of DNA topology and have been established molecular targets for several decades.(1,6,7) Topoisomerases relax the helical supercoiling of DNA that is generated during replication, transcription, and chromatin remodeling.(8,9)
Topoisomerase II (topo II) catalyzes an ATP-dependent reaction in which one DNA double helix is passed through another.(6) There are two topo II isozymes, topo IIα (170 kDa) and topo IIβ (180 kDa). The expression of topo IIα is high in the S phase and peaks in the late S/G2 phase of the cell cycle, whereas topo IIβ is expressed at a constant level throughout the cell cycle.(10)“Topo II poisons”, which are highly cytotoxic, stimulate and stabilize the formation of topo II–DNA cleavable complexes, leading to accumulation of these cleavable complexes.(11,12) In contrast, “topo II catalytic inhibitors” such as ICRF-187, disrupt enzyme activity without stabilizing the cleavable complex.(13,14) Etoposide (VP-16) is a topo II poison that has been used in the chemotherapy of non-small-cell lung cancer (NSCLC) and other cancers.(15–19) In previous studies it has been shown that etoposide induces double-strand breaks (DSBs) and triggers the DNA damage response (DDR).(20,21) Agents that induce DNA damage in cells can trigger a complex network known as the “checkpoint pathways”, thereby promoting cell cycle delay or arrest and allowing more time for DNA repair.(22,23) This intricate signaling network can be turned on by activation of ataxia telangiectasia mutated (ATM) protein kinase, which phosphorylates numerous downstream substrates.(24)
Lung cancer is the leading cause of cancer death worldwide. The standard dual agent chemotherapy improves survival rate.(25,26) Many clinical trials have tested the combination of cisplatin and etoposide with other drugs in treatment of NSCLC(27), and found the overall survival rate has not been improved significantly. QS-ZYX-1-61, a derivative of etoposide (VP-16), was synthesized in Dr. Kuo-Hsiung Lee’s Natural Products Research Laboratories (University of North Carolina, Chapel Hill, NC, USA). In previous studies,...