A Multimodal Genotoxic Anticancer Drug Characterized by Pharmacogenetic Analysis in Caenorhabditis elegans

Abstract

<jats:p>New anticancer therapeutics require extensive <jats:italic>in vivo</jats:italic> characterization to identify endogenous and exogenous factors affecting efficacy, to measure toxicity and mutagenicity, and to determine genotypes that result in therapeutic sensitivity or resistance. We used <jats:italic>Caenorhabditis elegans</jats:italic> as a platform with which to characterize properties of the anticancer therapeutic CX-5461. To understand the processes that respond to CX-5461-induced damage, we generated pharmacogenetic profiles for a panel of <jats:italic>C. elegans</jats:italic> DNA replication and repair mutants with common DNA-damaging agents for comparison with the profile of CX-5461. We found that multiple repair pathways, including homology-directed repair, microhomology-mediated end joining, nucleotide excision repair, and translesion synthesis, were needed for CX-5461 tolerance. To determine the frequency and spectrum of CX-5461-induced mutations, we used a genetic balancer to capture CX-5461-induced mutations. We found that CX-5461 is mutagenic, resulting in both large copy number variations and a high frequency of single-nucleotide variations (SNVs), which are consistent with the pharmacogenetic profile for CX-5461. Whole-genome sequencing of CX-5461-exposed animals found that CX-5461-induced SNVs exhibited a distinct mutational signature. We also phenocopied the CX-5461 photoreactivity observed in clinical trials and demonstrated that CX-5461 generates reactive oxygen species when exposed to UVA radiation. Together, the data from <jats:italic>C. elegans</jats:italic> demonstrate that CX-5461 is a multimodal DNA-damaging anticancer agent.</jats:p>

The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells

“…Proposed mechanisms underpinning therapeutic efficacy of CX-5461 include stabilizing G-quadruplexes (G4) and impeding topoisomerase II (TOP2) activity 9 – 11 . This could cause DNA damage, directly inducing mutations, yet the extent of its mutagenic potential has not been investigated in humans 12 .…”

Exploring the Potential of Lapatinib, Fulvestrant, and Paclitaxel Conjugated with Glycidylated PAMAM G4 Dendrimers for Cancer and Parasite Treatment

“…Lapatinib and fulvestrant were both functionalized by condensation with acid chloride, NPCF, as described elsewhere [56]. Briefly, 116.2 mg L (200 µmoles) was dissolved in 4 mL CHCl 3 and 50 µL pyridine.…”

“…The nematode Caenorhabditis elegans is a very attractive animal model to characterize the properties of anticancer therapeutics. The small size, ease of handling, and possibility of genetic modification of C. elegans provide a sophisticated in vivo platform that combines the technical advantages of a microorganism with the greater biological complexity of a multicellular organism [55,56]. C. elegans has been used successfully to test the activity of EGFR tyrosine kinase inhibitors [57], selective estrogen receptor degraders (SERDs) [58], and microtubule-stabilizing drugs [59]; therefore, the biological activity of the synthesized constructs was studied also in vivo on C. elegans.…”

Synthesis, Anticancer Potential and Comprehensive Toxicity Studies of Novel Brominated Derivatives of Bacterial Biopigment Prodigiosin from Serratia marcescens ATCC 27117

“…Although the anticancer potential of PG and other prodigiosins has been demonstrated through various modes of action, such as apoptosis [34], autophagy [15], cell cycle arrest [14], mitochondrial uncoupling [35], and migration inhibition [36], toxicity studies of PG are not readily available in the literature. The nematode Caenorhabditis elegans is a model system with well-known developmental stages [37] that can be utilized in anticancer drug discovery for toxicity, immunity, and pharmacogenetics studies, among others [38], so it represents a fitting model system for PG toxicity and safety research. In addition, zebrafish (Danio rerio) are commonly used in drug screens, as the transparency of embryos for up to 5 days post fertilization facilitates visualization of potential toxicities [39,40].…”