Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

Abstract

Podophyllotoxin (PTOX) is a biologically active compound derived from the podophyllum plant, and both it and its derivatives possess excellent antitumor activity. The PTOX derivatives etoposide (VP-16) and teniposide (VM-26) have been approved by the U.S. Food and Drug Administration (FDA) for cancer treatment, but are far from perfect. Hence, numerous PTOX derivatives have been developed to address the major limitations of PTOX, such as systemic toxicity, drug resistance, and low bioavailability. Regarding their anticancer mechanism, extensive studies have revealed that PTOX derivatives can induce cell cycle G2/M arrest and DNA/RNA breaks by targeting tubulin and topoisomerase II, respectively. However, few studies are dedicated to exploring the interactions between PTOX derivatives and downstream cancer-related signaling pathways, which is reasonably important for gaining insight into the role of PTOX. This review provides a comprehensive analysis of the role of PTOX derivatives in the biological behavior of tumors and potential molecular signaling pathways, aiming to help researchers design and develop better PTOX derivatives.

Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives

“…The structure of PTOX contains five rings (A–E) and four consecutive chiral centers (C1–C4), 12 which exert strong pharmacological activities in cancer cells by inhibiting microtubule assembly and type II topoisomerase (TOP2) degradation. 35 The research and development of PTOX new drugs is a hot spot around the world, impelling researchers to design and synthesize derivatives with less cytotoxicity and drug resistance through structural modification, as well as separation from natural plants. In these efforts, anti-cancer types, activities, and mechanisms of different structurally modified compounds have been revealed, providing more basis for the clinical application of these potent drugs.…”

Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

“…Ketotifen is a histamine H1 receptor antagonist and used as an anti-allergic compound but not suitable for oral administration due to its acute toxicity 18 . Podophyllotoxin is used for many years for topical treatment of warts and for cancer recently due to its activity in inducing cell cycle arrest 19 , 20 . Some drugs, such as streptomycin and methyldopate, are clinically applicable but have frequent or severe side effects after long-term application 21 , 22 .…”

The Cytoprotective, Cytotoxic and Nonprotective Functional Forms of Autophagy Induced by Microtubule Poisons in Tumor Cells—Implications for Autophagy Modulation as a Therapeutic Strategy

“…Podophyllotoxins (PTOX) are a subclass of plant secondary metabolites known as lignans that present in the resin of Podophyllum plants. PTOX antitumor properties are attributed to both the ability to disrupt microtubules and the inhibition of topoisomerase II [ 56 , 57 ]. PTOX inhibits the assembly of microtubules by targeting the colchicine binding site, which results in the inhibition of the polymerization of microtubule proteins as well as causing G2/M cell cycle arrest [ 58 ].…”

“…PTOX inhibits the assembly of microtubules by targeting the colchicine binding site, which results in the inhibition of the polymerization of microtubule proteins as well as causing G2/M cell cycle arrest [ 58 ]. In addition, some PTOX derivatives, such as etoposide and teniposide, have the ability to stabilize the cleavage complex between topoisomerase II and its DNA substrate, which results in DNA breakage, ultimately resulting in tumor cell death via the accumulation of chromosomal damage [ 56 , 59 ].…”