A study of the cytotoxic activities of two polyacrylic acid-based compounds containing gold (aurumacryl) and silver (argacryl) against a panel of human tumor cell cultures (769-P, Caki-2, SK-RC-1 renal carcinoma lines, BT-474 breast carcinoma, and NCI-H211 small cell lung carcinoma) was carried out in vitro. The results we obtained were analyzed in comparison with the data established earlier for other cell cultures (MCF-7 breast carcinoma, A-549 lung carcinoma, HCT116 colon carcinoma, and Mel Me melanoma). The IC50 cytotoxic index of drugs for the nine tested tumor cell lines ranged from 0.8 to 5.2 μg/mL for aurumacryl and from 0.2 to 14.4 μg/mL for argacryl (in terms of gold and silver content, respectively), depending on the type of tumor. Significant differences were found in the spectra of the lethal effects of aurumacryl and argacryl against tumor cells of various types.

The article presents the generalized results from studies on antitumor activity, cytotoxic effects and mechanisms of action of gold (aurumacryl) and silver (argacryl) polyacrylates in the context of modern ideas about perspectives on the possible use of gold and silver-containing compounds as potential antitumor drugs that showed promising results in experimental studies.

Silver polyacrylate (argacryl) exerts antitumor activity against murine solid tumors in vivo and exhibits cytotoxic effects on human tumor cells in vitro. Argacryl enhances the antitumor effect of cisplatin (a murine Lewis lung carcinoma cell line) and does not show cross-resistance to cisplatin and doxorubicin (MCF-7, human breast cancer cells). The molecular mechanism of action of argacryl is associated with the induction of DNA single-strand breaks in the absence of cross-linking in the DNA molecule.

Nitrosonium cations (NO+ ) are short-lived, so we hypothesized that they cause double-strand (DS) DNA breaks in the early stages of incubation of the NO+ donor with cells. By MTT-test and DNA-comet, methods on human breast cancer cells MCF-7 has been shown that the donor NO+ sodium nitroprusside leads to rapid cyto- and genotoxic effects before the start of reparative processes in the cells. The MTT-test showed the involvement of the NER repair mechanism in the occurrence of DS and a possible contribution to the genotoxic effect of NO+ .

The cytotoxic effect of dinitrosyl iron complex (DNIC) with mercaptosuccinate (MS) on MCF-7 human tumor cells is twice as great as the cytotoxic effect of the mixture of precursors of its synthesis (MS + Fe2+). It has been shown by the alkaline comet assay that the mixture (MS + Fe2+) induced single-strand breaks (SSBs) in DNA in cells. These lesions were completely repaired after 24 h. Although the DNIC–MS complex induced fewer SSBs in the cell DNA compared with the mixture, some of them remained unrepaired in 19

The cytotoxic activity of metal polyacrylates containing gold (aurumacryl) or silver (argacryl) has been studied in human breast cancer cell cultures sensitive (MCF-7) and resistant to cisplatin (MCF-7/CP) and doxorubicin (MCF-7/ADR) with parallel evaluation of the cytotoxicity of cisplatin and doxorubicin against these cell lines. Cells resistant to cisplatin and doxorubicin retain full sensitivity to the cytotoxic effects of aurumacryl and argacryl. The metal polyacrylates show no cross-resistance relationship with cisplatin or doxorubicin in the MCF-7 cell culture model.

Abstract—The antitumor and cytotoxic actions of the binuclear dinitrosyl iron complex with N-acetylcysteine have been investigated by using a mouse solid tumor (Acatol adenocarcinoma), human tumor cell cultures (MCF-7 human breast cancer and A549 human lung cancer), and normal human cells (WI-26 skin fibroblast cell line) as in vivo and in vitro models. After intravenous or intraperitoneal administration, the complex inhibits Acatol tumor growth by 60% as compared to the control. The medication exerts a mild cytotoxic effect on both tumor and healthy cells. The IC50 values for tumor cells MCF-7 and A549 and for human skin fibroblasts are 0.12, 0.44, and 0.28 μM/mL, respectively. It is assumed that the antitumor effects of medications with binuclear dinitrosil iron complexes is due not only to their direct cytotoxic effect on tumor cells but also to the indirect influence of nitric oxide donors on tumor growth associated with their ability to be engulfed by immunocompetent cells of the body, which target the complexes to the tumor.

Проведено сравнительное изучение цитотоксической активности двух полимерных соединений на основе полиакриловой кислоты, содержащих золото (аурумакрил) и серебро (аргакрил), в отношении опухолевых (рак молочной железы MCF-7, рак легкого А-549, рак толстой кишки HCT116, меланома Mel Me) и нормальных (фибробласты кожи hFB-hTERT6) клеток человека in vitro. Показатель цитотоксического эффекта IC50 варьирует в пределах от 13 до 65 мкг/мл и от 25 до 180 мкг/мл для аурумакрила и аргакрила соответственно, изменяясь в зависимости от типа опухолевых клеток. Наибольшую чувствительность к действию препаратов проявляют клетки рака молочной железы MCF-7.

Abstract —The cytotoxic activities of two polyacrylate-based polymer compounds containing gold (aurumacryl) and silver (argacryl) against malignant (MCF-7 breast cancer, A-549 lung cancer, HCT116 colon cancer, and Mel Me melanoma) and healthy (skin fibroblasts hFB-hTERT6) human cells have been studied in vitro and compared. The IC 50 cytotoxicity indices of aurumacryl and argacryl vary within 13–65 and 25–180 μg/mL, respectively, depending on tumor cell type. The greatest sensitivity to the drugs was recorded in MCF-7 breast cancer cells.

We compared the antitumor and cytotoxic activities of two polyacrylic acid-based compounds containing gold (aurumacryl) and silver (argacryl). The tested substances successfully inhibit the growth of some solid tumors in mice (Lewis lung carcinoma, Acatol adenocarcinoma, and Ca-755 adenocarcinoma) and exert pronounced cytotoxic activity against human tumor cells (MCF-7 cell culture). The coefficient of murine tumor growth inhibition varies between 55 and 90% with reference to the control. The index of the cytotoxic effect, IC50, is 25 μg/mL and 100 μg/mL for argacryl and aurumacryl, respectively. The sensitivity of animal tumor cells in vivo and human tumor cells in vitro to the tested substances depends on the nature of the metal coordinated in the polymer compound.

Проведено сравнительное изучение противоопухолевой и цитотоксической активности двух полимерных соединений на основе полиакриловой кислоты, содержащих золото (аурумакрил) и серебро (аргакрил). Препараты эффективно ингибируют развитие солидных опухолей мышей (карцинома легких Льюис, аденокарцинома Акатол, аденокарцинома Са-755) и обладают выраженным цитотоксическим эффектом в отношении клеток опухоли человека (культура клеток MCF-7). Коэффициент торможения роста опухолей мышей колеблется в пределах от 55 до 90% по сравнению с контролем. Показатель цитотоксического эффекта ИК50 составляет 25 мкг/мл и 100 мкг/мл для аргакрила и аурумакрила соответственно. Чувствительность к препаратам клеток опухолей животных in vivo и клеток опухоли человека in vitro зависит от природы металла в комплексном полимерном соединении.

Исследована противоопухолевая активность и цитотоксический эффект биядеpных динитpозильных комплексов железа с N-ацетилцистеином в условиях in vivo и in vitro на модели солидной опухоли мышей (аденокарцинома Акатол), на моделях клеточных культур опухолей человека (рак молочной железы MCF-7, рак легкого А549) и нормальных клеток человека (фибробласты кожи линии WI-26). Установлено, что препарат, содержащий эти комплексы, ингибирует развитие опухоли Акатол на 60% по сравнению с контролем как при внутривенном, так и при внутрибрюшинном введении. Препарат обладает слабо выраженным цитотоксическим эффектом как в отношении опухолевых, так и нормальных клеток. Показатель ИК50 составляет 0.12 и 0.44 мкМ/мл для опухолевых клеток MCF-7 и А549 соответственно, а для фибробластов кожи человека - 0.28 мкМ/мл. Предполагается, что противоопухолевый эффект препаратов на основе биядерных динитрозильных комплексов железа обусловлен не только их прямым цитотоксическим воздействием на опухолевые клетки, но и опосредованным влиянием доноров оксида азота на развитие опухоли, связанным с их способностью включаться в иммунокомпетентные клетки организма, обеспечивающие направленную доставку комплексов к опухолям.

The cytotoxic effect of the potential antitumor drug aurumacryl (gold polyacrylate) on human skin fibroblast cell line hFB-hTERT6 has been studied in vitro. It has been found that aurumacryl exhibits substantial cytotoxicity to human skin fibroblasts. The maximum cytotoxic effect (75% cell death) is observed at an aurumacryl concentration of 0.125 mg/mL. The inhibitory concentration of aurumacryl that causes 50% human skin fibroblast death ( IC 50 ) is 0.09 mg/mL.

Systemic administration of N-methyl-N-nitrosourea in rats resulted in the death of retinal photoreceptors followed by differentiation of retinal Müller glial cells into photoreceptor-like cells [ 27 ]. However, mammalian Müller glial cells exhibit an extremely limited proliferative capacity, which correlates with the expression of histone γH2AX and p21 protein. These proteins are known to be components of the cellular response to DNA damage [ 26 ]. The restriction of proliferation of human Müller glial cells prevents retinal replacement therapy by cell transplantation. On the other hand, the mechanism that limits the proliferation of Müller glia in the mammalian retina remains to be elucidated. We examined the Müller glial proliferative response and the DNA damage response in Müller glia in the postreplicative stage, as well as the expression of the p53 protein in response to the influence of retinotoxic N-methyl-N-nitrosourea. It was shown that N‑methyl-N-nitrosourea induced retinal degeneration in mice via apoptosis of photoreceptors, whereas the other retinal layers retained intact morphology. Nevertheless, the formation of DNA breaks and alkali-labile sites was observed in all retinal cells 5 h after the N-methyl-N-nitrosourea injection; these formations completely disappeared 15 h after N-methyl-N-nitrosourea injection. By 72 h, a significant increase in the number of DNA breaks in Müller glial cells was observed. The absence of bromodeoxyuridine incorporation into the retinal cells later testifies to the absence of proliferation of Müller glial cells and DNA repair synthesis. At the same time, an increased expression of the p53 protein, a universal marker of DNA damage, was observed in the retina. Thus, our findings support the concept of the “DNA damage response” with respect to Müller glial cells, according to which the DNA damage in Müller glial cell is related to the restricted proliferation of these cells in mice. Postreplicative repair is considered as a probable mechanism of the formation of DNA breaks in postreplicative Müller glial cells.

The influence of the nature of the ligands of nitric oxide-generating compounds, such as binuclear dinitrosyl iron complexes containing glutathione or mercaptosuccinate, on their tumor growth-inhibiting and cytotoxic effects has been studied in vivo and in vitro. The antitumor effect of the complex with glutathione exceeds that exerted by the complex with mercaptosuccinate. These complexes inhibit tumor growth (Lewis lung carcinoma) by 90 and 65%, respectively, compared to the control. These complexes are weakly cytotoxic against the MCF-7 human cancer cell line. The half-maximum inhibitory concentration of the complex with mercaptosuccinate at which the survival of cells is reduced by 50% (IC50) is 0.8 μmol/mL (640 μg/mL), whereas in the case of the complex with glutathione it is 2 μmol/mL (1600 μg/mL). It is assumed that the antitumor activity of iron complexes is determined by their ability to enter immunocompetent cells, which provide a direct route to tumor tissues.

Introduction. The investigation of metal substituted organic compounds as potential antitumor drugs is one of the promising areas of research in experimental and clinical oncology. Objective. The pre-clinical study of the original antitumor drug aurum polyacrylate (aurumacryl) which belongs to such new for oncology group of compounds as polyacrylates of metals was the aim of this work. Materials and methods.  Aurumacryl antitumor activity was determined as the tumor growth inhibitory effect against some of the murine solid tumors (Lewis lung carcinoma, Acatol adenocarcinoma and Ca-755 adenocarcinoma). Drug cytotoxic effect against some of the human tumor cells (Mel-Mo melanoma, A549 lung carcinoma, MCF-7 breast carcinoma, HCT116 colon adenocarcinoma) was evaluated with standard МТТ-test. The aurumacryl pharmacokinetics in tumor bearing mice (Lewis lung carcinoma) was studied. The inductively coupled plasma mass spectrometry method was used for the estimation of the aurum maintenance in the tested tissues (tumor, blood, kidneys, liver, lungs, spleen, brain). Results. The 80–90 % tumor growth inhibitory effect of aurumacryl against some solid tumors in mice had been revealed in vivo as well as the death of the 60–90 % human tumor cells of various origins in vitro. Beside this the strong decrease of the number of proliferating MCF-7 tumor cells had been shown. The distribution of aurumacryl in the body of the mice with the solid tumor had been revealed. Conclusion. On the base of the data obtained the further study of the aurumacryl as a potential antitumor agent seems rather promising.

Introduction. The investigation of metal substituted organic compounds as potential antitumor drugs is one of the promising areas of research in experimental and clinical oncology.Objective. The pre-clinical study of the original antitumor drug aurum polyacrylate (aurumacryl) which belongs to such new for oncology group of compounds as polyacrylates of metals was the aim of this work.Materials and methods. Aurumacryl antitumor activity was determined as the tumor growth inhibitory effect against some of the murine solid tumors (Lewis lung carcinoma, Acatol adenocarcinoma and Ca-755 adenocarcinoma). Drug cytotoxic effect against some of the human tumor cells (Mel-Mo melanoma, A549 lung carcinoma, MCF-7 breast carcinoma, HCT116 colon adenocarcinoma) was evaluated with standard МТТ-test. The aurumacryl pharmacokinetics in tumor bearing mice (Lewis lung carcinoma) was studied. The inductively coupled plasma mass spectrometry method was used for the estimation of the aurum maintenance in the tested tissues (tumor, blood, kidneys, liver, lungs, spleen, brain).Results. The 80–90 % tumor growth inhibitory effect of aurumacryl against some solid tumors in mice had been revealed in vivo as well as the death of the 60–90 % human tumor cells of various origins in vitro. Beside this the strong decrease of the number of proliferating MCF-7 tumor cells had been shown. The distribution of aurumacryl in the body of the mice with the solid tumor had been revealed.Conclusion. On the base of the data obtained the further study of the aurumacryl as a potential antitumor agent seems rather promising.

The cytotoxic effect of the potential antitumor drug aurumacryl (aurum polyacrylate) on the hFB-hTERT6 human skin fibroblast cell line has been studied in vitro. It has been established that aurumacril exhibits substantial cytotoxicity to human skin fibroblasts. The maximum of cytotoxic effect (75% cell death) was observed when the concentration of aurumacryl was 0.125 mg/ml. The inhibitory concentration of aurumacryl causing 50% human skin fibroblast death (IC50) was 0.09 mg/ml.

Работа поддержана РФФИ (гранты № 18-015-00125, 18-515-00004, 19-015-00444 и 18-34-00561_мол_а) и БРФФИ (гранты Б18Р-058)