Abstract
Fascaplysin, the natural product of a marine sponge, exhibits anticancer activity against a broad range of tumor cells, presumably through interaction with DNA, and/or as a highly selective cyclin-dependent kinase 4 (CDK4) inhibitor. In this study, cytotoxic activity of fascaplysin against a panel of small cell lung cancer (SCLC) cell lines and putative synergism with chemotherapeutics was investigated. SCLC responds to first-line chemotherapy with platinum-based drugs/etoposide, but relapses early with topotecan remaining as the single approved therapeutic agent. Fascaplysin was found to show high cytotoxicity against SCLC cells and to induce cell cycle arrest in G1/0 at lower and S-phase at higher concentrations, respectively. The compound generated reactive oxygen species (ROS) and induced apoptotic cell death in the chemoresistant NCI-H417 SCLC cell line. Furthermore, fascaplysin revealed marked synergism with the topoisomerase I-directed camptothecin and 10-hydroxy-camptothecin. The Poly(ADP-ribose)-Polymerase 1 (PARP1) inhibitor BYK 204165 antagonized the cytotoxic activity of fascaplysin, pointing to the involvement of DNA repair in response to the anticancer activity of the drug. In conclusion, fascaplysin seems to be suitable for treatment of SCLC, based on high cytotoxic activity through multiple routes of action, affecting topoisomerase I, integrity of DNA and generation of ROS.
Highlights
Fascaplysin (12,13-Dihydro-13-oxopyrido[1,2-a:3,4-b′]diindol-5-ium chloride), a red bis-indole alkaloid of the marine sponge Fascaplysinopsis Bergquist sp., was first isolated in 1988, byRoll et al [1]
GLC14, 16 and 19 comprise a series of small cell lung cancer (SCLC) cell lines obtained from a single patient prior to chemotherapy and after first-line and second-line therapy, respectively
SCLC cell line with IC50 values for cisplatin of 1.2 ± 0.6 and for etoposide of 0.5 ± 0.2, respectively, NCI-H417 and DMS153 are chemoresistant with IC50 values of 12.0 ± 2.8/3.3 ± 0.9 for cisplatin and 15.1 ± 2.2/12.9 ± 0.5 for etoposide, respectively
Summary
Roll et al [1] This compound exhibited a broad range of activities including antibacterial, antifungal, antiviral, antimalarial, antiangiogenic and antiproliferative activity against numerous cancer cell lines [2,3,4]. Fascaplysin showed promising specific cyclin-dependent kinase 4 (CDK4) inhibitory activity with IC50 of 0.35 μM and it correspondingly blocked the growth of various cancer cells at the G0/1 phase of cell cycle [6,7]. Shafiq and co-workers confirmed the specific effect of this compound on CDK4, which is known to play a key role in cell cycle control and is an important target for anticancer drugs [8]. The NCI60 panel misses small cell lung cancer (SCLC) cell lines altogether, a tumor entity that accounts for a significant fraction of lung cancer deaths [9]
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