Antitumoral Effect of Plocabulin in High Grade Serous Ovarian Carcinoma Cell Line Models

Abstract

Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation.

Effect of the Marine Polyketide Plocabulin on Tumor Progression

“…Plocabulin showed cytotoxic activity towards ovarian cancer cell lines with different sensitivities to cisplatin treatment [ 21 ], including the very resistant cells PEA1, PEA2, PEO4, OV866(2), with IC 50 in the low nM range ( Table 1 ). Thus, plocabulin may be a promising treatment in cells resistant to conventional chemotherapeutic regimen.…”

“…Thus, plocabulin may be a promising treatment in cells resistant to conventional chemotherapeutic regimen. In the same panel of high-grade serous ovarian carcinoma cell lines, the anticancer effects of plocabulin were assessed in 3D spheroids [ 21 ]. Three-dimensi0onal cell cultures are used in cancer research as a bridge between in vitro and in vivo experimental models.…”

“…The lower diffusion gradient of the drug through the structure of the spheroid and the different distribution of oxygen, nutrients, and catabolites compared to the monolayer cultures reduce drug response in 3D cells [ 26 ]. Thus, it is not surprising that plocabulin only remained cytotoxic in the low nanomolar range in 3 of the 11 cell lines in the spheroid model ( Table 1 ), even if the study tested plocabulin activity of up to 10 nM and not at higher concentrations [ 21 ]. The anti-invasion and anti-migration capacity of plocabulin was tested in both 2D and 3D models.…”

“…The anti-invasion and anti-migration capacity of plocabulin was tested in both 2D and 3D models. Plocabulin reduced both transwell cell migration and invasion in PEO14, OV866(2) and PEA2 monolayer cells, while only a weak effect was recorded in OV866(2) spheroids [ 21 ]. This is the first evidence supporting the anti-migratory properties of plocabulin in 3D models, and requires further investigation.…”

“…Moreover, the same study explored the combination of plocabulin with conventional chemotherapeutic drugs commonly used for the treatment of high-grade serous ovarian cancer, i.e., cisplatin, gentamicine, doxorubicin, trabectedin. None of the tested combinations showed synergistic or additive effects using the robust and restrictive tool SynergyFinder Plus score [ 21 ].…”