A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non–Small Cell Lung Cancer Cells

Abstract

The therapeutic effect in non–small cell lung cancer (NSCLC) patients is limited because of intrinsic and acquired resistance. Thus, an unmet need exists for the development of new drugs to improve the therapeutic efficacy in NSCLC patients. In this study, the novel small molecule indolizino[6,7-b]indole derivative BO-1978 was selected to evaluate its therapeutic effects on NSCLC and its preclinical toxicity in animal models. An in vitro cytotoxicity assay revealed that BO-1978 significantly suppressed the growth of various NSCLC cell lines with or without mutations in epidermal growth factor receptor (EGFR). Mechanistically, we demonstrated that BO-1978 exhibited multiple modes of action, including inhibition of topoisomerase I/II and induction of DNA cross-linking. Treatment of NSCLC cells with BO-1978 caused DNA damage, disturbed cell cycle progression, and triggered apoptotic cell death. Furthermore, BO-1978 significantly suppressed the growth of EGFR wild-type and mutant NSCLC tumors in xenograft tumor and orthotopic lung tumor models with negligible body weight loss. The combination of BO-1978 with gefitinib further suppressed EGFR mutant NSCLC cell growth in xenograft tumor and orthotopic lung tumor models. Preclinical toxicity studies showed that BO-1978 administration did not cause apparent toxicity in mice. Based on its significant therapeutic efficacy and low drug toxicity, BO-1978 is a potential therapeutic agent for treatment of NSCLC.

A Low-Toxicity DNA-Alkylating N-Mustard-Quinoline Conjugate with Preferential Sequence Specificity Exerts Potent Antitumor Activity Against Colorectal Cancer

“…In this study, the assays of cytotoxicity, alkaline agarose gel shift, comet and modified comet, flow cytometry, and annexin V staining were performed according to protocols as previously described [24] , [25] . Details are provided in Supplementary Materials and Methods .…”

“…Animal studies including anticancer activity in xenograft mouse models and the toxicology examination in ICR mice are described in Supplementary Materials and Methods [24] .…”

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

“…To overcome the multi-drug resistance in NSCLC patients, Chen et al adapted the above strategy and developed hybrid molecules to improve drug efficacy. They designed and synthesized a series of indolizino [6,7-b]indoles, incorporating two pharmacophores: β-carboline group and a bis(hydroxymethyl)pyrrole group with topoisomerase (Topo) I/II inhibition and DNA cross-linking abilities respectively [81,82] (Figure 8). The hybrid derivative (BO-1978) was found to be effective in the suppression of lung adenocarcinoma A549 cells through the inhibition of Topo I/II and the induction of DNA cross-links resulting in DNA damage and a resulting cell cycle arrest.…”

“…The hybrid derivative (BO-1978) was found to be effective in the suppression of lung adenocarcinoma A549 cells through the inhibition of Topo I/II and the induction of DNA cross-links resulting in DNA damage and a resulting cell cycle arrest. The hybrid derivative (BO-1978) was synthesized as shown in Scheme 8 [81,82]. Scheme 7.…”

Scutellarin induces apoptosis and autophagy in NSCLC cells through ERK1/2 and AKT Signaling Pathways in vitro and in vivo

“…Non-small cell lung cancer (NSCLC) accounts for greater than 80% of lung cancer, with a low 5-year survival rate 2 . Recent treatments, mainly including surgery, chemotherapy and targeted therapy, however, have not been ultimately changed the dismal overall survival rate 3 . Therefore, understanding of the molecular mechanisms and exploiting promising therapeutic agents for NSCLC is urgently required.…”