A Nitrocarbazole as a New Microtubule-Targeting Agent in Breast Cancer Treatment

Abstract

Breast cancer is still considered a high-incidence disease, and numerous are the research efforts for the development of new useful and effective therapies. Among anticancer drugs, carbazole compounds are largely studied for their anticancer properties and their ability to interfere with specific targets, such as microtubule components. The latter are involved in vital cellular functions, and the perturbation of their dynamics leads to cell cycle arrest and subsequent apoptosis. In this context, we report the anticancer activity of a series of carbazole analogues 1–8. Among them, 2-nitrocarbazole 1 exhibited the best cytotoxic profile, showing good anticancer activity against two breast cancer cell lines, namely MCF-7 and MDA-MB-231, with IC50 values of 7 ± 1.0 and 11.6 ± 0.8 μM, respectively. Furthermore, compound 1 did not interfere with the growth of the normal cell line MCF-10A, contrarily to Ellipticine, a well-known carbazole derivative used as a reference molecule. Finally, in vitro immunofluorescence analysis and in silico studies allowed us to demonstrate the ability of compound 1 to interfere with tubulin organization, similarly to vinblastine: a feature that results in triggering MCF-7 cell death by apoptosis, as demonstrated using a TUNEL assay.

Annona cherimola Mill. Leaf Extracts Affect Melanoma Cells Growth and Progression

“…Last but not least, the cytoskeleton, a complex intracellular structure, vital for many cell processes, is strictly connected, as well, with the tumor progression and the EMT process. Among the numerous components, two major ones are tubulin and actin which have been targets of potent anti-cancer drugs, from natural sources or chemical synthesis [ 29 , 44 , 45 , 46 ]. The reorganization of the actin cytoskeleton is fundamental for the migration and invasion of cancer cells, and has recently attracted the interest of many research groups, while the microtubule network provides the driving force for cell migration [ 47 ].…”

5,8-Dimethyl-9H-carbazole Derivatives Blocking hTopo I Activity and Actin Dynamics

“…These results are in agreement with literature studies [ 12 , 18 , 48 ] reporting that different carbazole derivatives may block both the hTopos or, selectively, only one and induce cancer cells death. Amongst the targets of carbazole derivatives, cytoskeletal proteins have attracted the attention of many researchers, and some of them were found to provoke a net disorganization of the tubulin filaments and their accumulation around cell nuclei [ 22 , 49 , 50 ]. However, the literature is still lacking studies reporting the effects on the actin metabolism, with the exception, e.g., of a study on cell motility exerted by the carbazole derivative wiskostatin.…”

“…These findings are seminal in the fight against breast cancer, which still represents the main cancer-related cause of disease for women, and its incidence and mortality have risen worldwide in recent years [ 19 ]. Over the years, numerous carbazole derivatives were designed, synthesized, and examined for their anti-breast cancer activity [ 20 , 21 , 22 ]. Recently, Vlaar et al studied new analogues of EHop-016, a carbazole compound acting as a Rac1 inhibitor, implicated in the intracellular actin polymerization.…”

Exploring the anticancer and antioxidant properties of Vicia faba L. pods extracts, a promising source of nutraceuticals

“…Cells were seeded in 48-well culture plates containing glass slides and then serum-deprived for 24 h and incubated with the most active extracts for 24 h (concentration equal to their IC 50 value). The cells were incubated with primary antibody, as previously described ( Ceramella et al, 2019 ; Sinicropi et al, 2021 ). The rabbit anti β-Tubulin were purchased from Santa Cruz Biotechnology and diluted 1:100 before the use.…”