Etoposide's Biochemical Mechanisms; Cell Death Upshot

Abstract

Etoposide is a semisynthetic epipodophyllotoxin derivative widely used as an antineoplastic agent for the treatment of several malignancies, including small-cell lung cancer, testicular cancer, lymphomas, and pediatric tumors. This review provides an overview of the molecular mechanisms underlying the therapeutic activity, cellular transport, metabolism, apoptosis, and resistance associated with etoposide. The primary target of etoposide is DNA topoisomerase II, whose inhibition stabilizes the enzyme–DNA cleavage complex and promotes persistent DNA double-strand breaks, replication stress, cell-cycle arrest, and apoptotic cell death. Etoposide-induced DNA damage activates ATMand ATR-mediated signaling, resulting in checkpoint activation and regulation of p53, p21, and other downstream effectors. Apoptosis occurs through both intrinsic and extrinsic pathways involving Bax, PUMA, cytochrome c, caspases, death receptors, and mitochondrial dysfunction. Additional signaling mechanisms involving ceramide, ASK1, MEKK1, JNK, p38 MAPK, c-Abl, and p73 further contribute to cellular responses. Conversely, activation of Ras/Raf/MEK/ERK and PI3K/Akt survival pathways, together with ABC transporter-mediated drug efflux and altered metabolism, contributes to etoposide resistance. Understanding these interconnected mechanisms may support the development of rational combination therapies and novel strategies to overcome resistance and enhance the clinical effectiveness of etoposide.