A Novel Inhibitor of Topoisomerase I Is Selectively Toxic for a Subset of Non–Small Cell Lung Cancer Cell Lines

Abstract

SW044248, identified through a screen for chemicals that are selectively toxic for NSCLC cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was non-toxic to immortalized human bronchial cell lines. The acute transcriptional response to SW044248 in sensitive HCC4017 cells correlated significantly with inhibitors of topoisomerases and SW044248 inhibited topoisomerase 1 (Top1) but not topoisomerase 2. SW044248 inhibited Top1 differently than camptothecin and camptothecin did not show the same selective toxicity as SW044248. Elimination of Top1 by siRNA partially protected cells from SW044248, although removing Top1 was itself eventually toxic. Cells resistant to SW044248 responded to the compound by upregulating CDKN1A and siRNA to CDKN1A sensitized those cells to SW044248. Thus, at least part of the differential sensitivity of NSCLC cells to SW044248 is the ability to upregulate CDKN1A.

The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model

“…Moreover, further studies in tumor spheroids demonstrated that the combination with seeMet 12 mediated significant spheroid size reductions compared to sorafenib alone (Figures 3D,E). These results are in line with a recent study in melanoma, where it was demonstrated that HGF/MET signaling contributed to resistance to the BRAF inhibitor vemurafenib via activation of ERK-MAPK and PI3K-AKT, and that pharmacologic inhibition of the cMet/AKT pathway restored the sensitivity (37). Consequently, dual targeting of cMet and BRAF in colorectal cancer may be a promising concept, and should be further explored, in particular since it may also offer hope to overcome resistance of several targeted drugs.…”

Antitumor potential of a novel camptothecin derivative, ZBH-ZM-06

“…In addition, the CPT-11 prodrug group (4-piperidinyl piperidine) causes AchE inhibition, which easily leads to acetylcholine syndrome, resulting in early severe diarrhea and other sideeffects (10). In order to overcome the above drawbacks of CPT-11, scientists have made several attempts to improve it (10,(17)(18)(19). In the present study, we designed and synthesized a novel 10-hydroxy CPT prodrug with a high efficiency and low toxicity (20,21).…”

“…CPT-11 due to its low enzymatic conversion rate in vivo and its uncertain pharmacokinetic properties among individuals. In addition, the CPT-11 prodrug group (4-piperidinyl piperidine) causes AchE inhibition, which easily leads to acetylcholine syndrome, resulting in early severe diarrhea and other sideeffects (10). In order to overcome the above drawbacks of CPT-11, scientists have made several attempts to improve it (10,(17)(18)(19).…”

“…The US Food and Drug Administration has approved these CPT derivatives for ovarian and colon cancer treatment (8,9). Furthermore, their anticancer potential on other tumors also has been reported, such as lung (7,10), breast (11), pancreatic cancer (12), lymphoma (13), glioma (14) and leukemia (15).…”

Discovery of Novel Topoisomerase II Inhibitors by Medicinal Chemistry Approaches

“…This is why topo I inhibitors in clinical studies, such as camptothecin (CPT) and its derivatives topotecan, 10-hydroxy camptothecin (OPT), irinotecan (CPT-11), and rubitecan (9-NC), are normally toxic for rapidly growing tissues. Moreover, the cytotoxic essence of these drugs easily induces significant therapy-related secondary effects, including cardiotoxicity, myelosuppression, gastrointestinal toxicity, and even secondary leukemia . Hence, recent studies have concentrated on the exploitation of drugs or agents targeting topo II.…”