The pleiotropic activity of human cathelicidin LL-37 peptide includes an ability to suppress development of colon cancer cells. We hypothesized that the anticancer activity of LL-37 would improve when attached to the surface of magnetic nanoparticles (MNPs). Using colon cancer culture (DLD-1 cells and HT-29 cells), we evaluated the effects of MNPs, LL-37 peptide, its synthetic analog ceragenin CSA-13, and two novel nanosystems, ie, MNP@LL-37 and MNP@CSA-13, on cancer cell viability and apoptosis. Treatment of cancer cells with the LL-37 peptide linked to MNPs (MNP@LL-37) caused a greater decrease in cell viability and a higher rate of apoptosis compared with treatment using free LL-37 peptide. Additionally, we observed a strong ability of ceragenin CSA-13 and MNP@CSA-13 to induce apoptosis of DLD-1 cells. We found that both nanosystems were successfully internalized by HT-29 cells, and cathelicidin LL-37 and ceragenin CSA-13 might play a key role as novel homing molecules. These results indicate that the previously described anticancer activity of LL-37 peptide against colon cancer cells might be significantly improved using a theranostic approach.
Novel transition metal complexes (Au, Pd, Pt) with berenil and 2-(1-methyl-5-nitroimidazol-2-yl)ethanol were obtained through two-step synthesis. The cytotoxicity assay against MCF-7 and MDA-MB-231 breast cancer cells revealed that novel platinum and palladium complexes cause a reduction on the viability of MCF-7 and MDA-MB-231 breast cancer cells to a greater extent than cisplatin. The complexes showed lower cytotoxicity on normal MCF-10A human breast epithelial cells than on tumor cells. Furthermore, we observed that these complexes selectively concentrate in tumor cell mitochondria due to the characteristic for these cells increased membrane potential that may explain their increased proapoptotic activity. The activity of the synthesized compounds against topoisomerase type IIα and their increased impact on DNA defragmentation also were documented. The novel complexes also induced autophagosome changes and inhibited tumor growth in xenograft models (established using breast cancer cells).
Natural antimicrobial peptides and ceragenins, as non-peptide amphipathic mimics, have been proposed as anti-cancer agents. To date, it has been confirmed that cathelicidin LL-37 and ceragenin CSA-13, both in free form and immobilized on the surface of magnetic nanoparticles (MNP@LL-37, MNP@CSA-13) induce apoptosis in colon cancer cells. Nevertheless, the question remains whether ceragenins, as synthetic analogs of LL-37 peptide and mimicking a number of its properties, act as antineoplastic agents in breast cancer cells, where LL-37 peptide stimulates oncogenesis. Considering potential anticancer activity, we determined whether CSA-13 and MNP@CSA-13 might be effective against breast cancer cells. Our study provides evidence that both CSA-13 and MNP@CSA-13 decreased viability and inhibit proliferation of MCF-7 and MDA-MB-231 cells despite the protumorigenic properties of LL-37 peptide. Flow cytometry-based analyses revealed that ceragenin treatment results in increases in dead and PI-negative/low-viability cells, which was associated with glutathione (GSH) depletion and increased reactive oxygen species (ROS) generation followed by mitochondrial membrane depolarization, caspase activation, and DNA fragmentation. These findings demonstrate that both CSA-13 and MNP@CSA-13 cause disruption of the oxidative balance of cancer cells. This novel mechanism of ceragenin-mediated eradication of cancer cells suggest that these agents may be developed as a possible treatment of breast cancer.
The role of estrogen in breast cancer progression and activation of prolidase activity and HIF-1α led us to study the effect of estrogen on nuclear HIF-1α expression in breast cancer estrogen-dependent MCF-7 and estrogen-independent MDA-MB-231 cells. We have found that in MCF-7 cells (expressing α and β estrogen receptor) cultured without estrogen receptor activator (phenol red, estradiol), HIF-1α was down-regulated, compared to the cells cultured with estrogen receptor activator. This effect was not observed in MDA-MB-231 cells (expressing only β estrogen receptor), suggesting that α estrogen receptor is involved in down-regulation of HIF-1α. However, in MDA-MB-231 cells (expressing high prolidase activity) cultured in the presence of prolidase substrates, Gly-Pro or Gly-HyPro, HIF-1α expression was induced in a dose-dependent manner, independently of estrogen receptor activation. In MCF-7 cells (with constitutively low prolidase activity) the effect of studied iminodipeptides on HIF-1α expression was much less pronounced but it was estrogen-dependent, showing importance of prolidase activity in mechanism of this process. The data were supported by confocal microscopy bio-imaging of HIF-1α in nucleus of MCF-7 and MDA-MB-231 cells that were cultured in the presence and absence of estrogen activator and prolidase substrates. It suggests that estrogen receptor may represent important therapeutic target in pharmacotherapy of estrogen receptor positive breast cancer, while ECM degradation enzymes, including prolidase may represent target in pharmacotherapy of estrogen receptor negative breast cancers.
Integrin receptors are considered to be the key factors in carcinogenesis. αIIbβ3-Integrin (GP IIb/IIIa) is the main glycoprotein of the surface of platelets, its presence has also been noted on the certain cancer cell lines. The molecular mechanism of its action in cancer cells remains unknown. This study presents effects of two αIIbβ3-inhibitors: Abciximab and Eptifibatide on apoptosis, expression of proline oxidase (POX), signaling molecules ERK 1/2, transcription factor NF-κB and HIF-1α, vascular endothelial growth factor (VEGF) as well as DNA biosynthesis, collagen biosynthesis and prolidase activity in MCF-7 breast cancer cells. Both ligands induced apoptosis, however we found significant differences in molecular mechanism of action between tested αIIbβ3-inhibitors. These differences include expression of POX, HIF-1α, NF-κB,VEGF and collagen biosynthesis. Eptifibatide presented stronger proapoptotic activity in MCF-7 cells than Abciximab. Results of this study suggest that Eptifibatide may be considered as a novel candidate for development of new anticancer therapy.
The impact of estradiol on troglitazone (TGZ)-induced proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis was studied in wild-type and PRODH/POX-silenced estrogen receptor (ER) dependent MCF-7 cells and ER-independent MDA-MB-231 cells. DNA and collagen biosynthesis were determined by radiometric method, prolidase activity evaluated by colorimetric method, ROS production was measured by fluorescence assay. Protein expression was determined by Western blot and proline concentration by LC/MS analysis. PRODH/POX degrades proline yielding reactive oxygen species (ROS). Estrogens stimulate collagen biosynthesis utilizing free proline and limiting its availability for PRODH/POX-dependent apoptosis. TGZ cytotoxicity was highly pronounced in wild-type MDA-MB-231 cells cultured in medium without estradiol or in the cells cultured in medium with estradiol but deprived of ERβ (by ICI-dependent degradation), while in PRODH/POX-silenced cells the process was not affected. The TGZ cytotoxicity was accompanied by increase in PRODH/POX expression, ROS production, expression of cleaved caspase-3, caspase-9 and PARP, inhibition of collagen biosynthesis, prolidase activity and decrease in intracellular proline concentration. The phenomena were not observed in PRODH/POX-silenced cells. The data suggest that TGZ-induced apoptosis in MDA-MB-231 cells cultured in medium without estradiol or deprived of ERβ is mediated by PRODH/POX and the process is facilitated by proline availability for PRODH/POX by TGZ-dependent inhibition of collagen biosynthesis. It suggests that combined TGZ and antiestrogen treatment could be considered in experimental therapy of estrogen receptor negative breast cancers.
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