Tag Archives: doxorubicin
Curcumin boosts doxorubicin cytotoxicity in breast cancer cells
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1Department of Molecular Immunology, Palladin Institute of Biochemistry,
National Academy of Sciences of Ukraine, Kyiv;
2Department of Technologies of Medical Diagnostics and Treatment,
ESC “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Ukraine;
3Department of General and Soil Microbiology, D.K. Zabolontny Institute of Microbiology
and Virology, National Academy of Sciences of Ukraine, Kyiv;
4Department of Microbiology and Immunology,
ESC “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Ukraine
*e-mail: andriisiromolot@knu.ua
Received: 04 February 2026; Revised: 13 April 2026;
Accepted: 29 May 2026; Available on-line: 18 June 2026
Background. Breast cancer remains the leading cause of cancer mortality in women due to the resistance to chemotherapy and severe side effects of doxorubicin (Doxo). One of the approaches to overcome this problem is to search for phytocompounds that can enhance the efficacy of chemotherapy and prevent the development of side effects. Objective. This work aimed to investigate in vitro whether the polyphenol curcumin (Cur) from turmeric (Curcuma longa) in combination with the commercial drug Doxo-HCl can enhance the cytotoxic effect of Doxo on breast cancer cell lines MDA-MB-231 and MCF-7 and to exhibit chemoprotective activity against normal HEK-293 cells. Methods. Cell viability was assessed with MTT assay, apoptosis induction by flow cytometry with Annexin V–eGFP and PI, reactive oxygen species (ROS) generation by the DCFH-DA probe. The combination index (CI) calculation method and CompuSyn, Biosoft software were used to determine the synergism or antagonism of the components. Results. The study revealed dose-dependent cytotoxicity, increased ROS formation, and increased morphological aberrations in cells when using the combination of Cur with Doxo-HCl compared to Doxo-HCl. Cur acted as a chemosensitizer, which synergistically enhanced the antitumor activity of Doxo-HCl while simultaneously reducing its cytotoxic effects in normal cells by reducing ROS production. Conclusions. The use of Cur in combination with Doxo-HCl will likely reduce the effective therapeutic dose of Doxo and increase the effectiveness of breast cancer chemotherapy.
Curcumin exerts protective effects against doxorubicin-induced cardiotoxicity
O. О. Klymenko1*, T. I. Drevytska1, O. O. Gonchar1, K. V. Tarasova2,
V. I. Nosar1, V. Ye. Dosenko1, I. M. Mankovska1
1Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv;
2Bogomolets National Medical University, Kyiv, Ukraine;
*e-mail: klymenkooks2018@gmail.com
Received: 16 October 2024; Revised: 03 December 2024;
Accepted: 21 February 2025; Available on-line: 03 Marchy 2025
The mechanism of doxorubicin (Dox) cardiotoxicity involves different pathways, including oxidative stress and mitochondrial dysfunction. It’s supposed that pharmacological effect on HIF gene expression may protect the heart against the detrimental effects of the doxorubicin-induced injury. We hypothesized that the cardioprotective effects of Curcumin (Curc) are exerted by regulating HIF and its target genes expression. To test this, an in vitro model of Dox-induced injury to primary myocardial cardiomyocytes was used. Isolated Wistar rat neonatal cardiomyocytes were incubated in the culture medium for 24 h in control, either with Dox (0.5 μmol/ml) or Curc (20 μmol/ml), or in their combination in the same doses. Mitochondria were isolated from rat cardiomyocytes culture. It was demonstrated that cardiomyocytes exposure to Dox led to an increase in the activity of oxidative stress markers in isolated mitochondria, a decrease in the efficiency of the respiratory chain and phosphorylation processes, decline of membrane potential and the rate of K+ ions entry into mitochondria. Doxorubicin inhibited the expression of mRNA of both HIF-1α, 2α, 3α subunits and its important target genes PDK-1 and IGF-1 in mitochondria. A negative impact on the cardiomyocyte contractile activity was observed. The combined use of doxorubicin with curcumin led to an increase of cardiomyocytes viability and attenuation of oxidative stress in mitochondria, prevented the development of mitochondrial dysfunction and significantly improved the contractile activity of cardiomyocytes.
Biochemical and cellular mechanisms of immunogenic cell death
M. Klishch, N. Skorokhyd, R. Panchuk, R. Stoika*
Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine;
*e-mail: stoika@cellbiol.lviv.ua; stoika.rostyslav@gmail.com
Received: 26 April 2024; Revised: 11 September 2024;
Accepted: 21 November 2024; Available on-line: 17 December 2024
Immunogenic cell death (ICD) is a mode of programmed cell death that leads to the activation of anticancer immune response and determines the long-term success of anticancer therapies. Here, we provide a review of the known molecular and cellular mechanisms of ICD. Usually, solid tumor experimental models have been used in ICD studies. However, ascites tumor models may possess some advantages over them. The results of our investigation on the approbation of murine Nemeth-Kellner lymphoma as an experimental ascites tumor model for ICD studies are presented.
Apoptosis induction in human leukemia cells by novel 2-amino-5-benzylthiazole derivatives
N. S. Finiuk1,2, I. I. Ivasechko1, O. Yu. Klyuchivska1,
Yu. V. Ostapiuk3, V. P. Hreniukh2, Ya. R. Shalai2,
V. S. Matiychuk3, M. D. Obushak3,
A. M. Babsky2, R. S. Stoika1
1Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
2Ivan Franko National University of Lviv, Biology Faculty, Lviv, Ukraine;
3Ivan Franko National University of Lviv, Chemistry Faculty, Lviv, Ukraine;
e-mail: stoika@cellbiol.lviv.ua
Received: 21 December 2018; Accepted: 20 March 2019
Derivatives of 2-amino-5-benzylthiazole are heterocyclic pharmacophores that exhibit different pharmacological activities including anticancer action. The mechanisms of such action of these compounds are not clear. The aim of the present study was to investigate apoptosis induction, particularly DNA damage in human leukemia cells, by the novel synthesized thiazole derivatives ‒ 2,8-dimethyl-7-(3-trifluoromethyl-benzyl)pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-one (compound 1) and 7-benzyl-8-methyl-2-propylpyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-one (compound 2). Western-blot analysis, DNA comet assay in alkaline conditions, diphenylamine DNA fragmentation assay, agarose gel retardation, and methyl green DNA intercalation assays were used to study the effects of the studied compounds in human leukemia cells. These compounds induced PARP1 and caspase 3 cleavage in the leukemia cells, also increased the level of pro-apoptotic Bim protein and the mitochondrion-specific EndoG nuclease, and decreased the level of the anti-apoptotic Bcl-2 protein. They caused DNA single-strand breaks and DNA fragmentation in the leukemia cells without direct DNA binding or DNA intercalation. Thus, novel 2-amino-5-benzylthiazole derivatives may be promising agents for apoptosis induction in the targeted human leukemia cells.
Targeting of the pro-oxidant-antioxidant balance in vitro and in vivo by 4-thiazolidinone-based chemotherapeutics with anticancer potential
L. Kobylinska1, O. Klyuchivska2, R. Lesyk1, R. Stoika2
1Danylo Halytsky Lviv National Medical University, Ukraine;
2Institute of Cell Biology, Lviv, Ukraine;
e-mail: lesya8@gmail.com
Received: 05 January 2019; Accepted: 20 March 2019
Oxidative stress is one of the main mechanisms by which anticancer chemotherapeutics damage normal tissues and organs. At the same time, it is an important biochemical mechanism of the neoplastic action of such medicines. The aim of the present study was to determine the pro-oxidant-antioxidant balance in vitro and in vivo under the influence of novel 4-thiazolidinone-based chemotherapeutics with anticancer potential. An advantage of using these compounds in vivo is their low general toxicity, compared to doxorubicin (Kobylinska L. et al., 2014, 2015, 2016). The 4-thiazolidinone derivatives (Les-3288, Les-3833, Les-3882) with previously established anti-neoplastic activity in vitro (Kobylinska L. et al., 2016) and antitumor effect in vivo (Kobylinska L. et al., 2018) were synthesized, dissolved in dimethyl sulfoxide, and administered intraperitoneally to Wistar rats daily for 20 days. Doses of the injected drugs equaled 10% of the LD50, namely doxorubicin – 5.5 mg/kg, Les-3882 and Les-3833 – 10.7 mg/kg, and Les-3288 – 24.3 mg/kg. The radical scavenging of 1,1-diphenyl-2-picrylhydrazil (DPPH) activity was measured. Concentrations of thio-barbituric acid-active products were assessed in blood serum, liver, heart and kidney tissues of treated rats. Additionally, the activities of superoxide dismutase, catalase and glutathione peroxidase were measured in blood serum and these tissues. We found that administration for 20 days of Les-3288, Les-3833 and Les-3882 compounds disturbed the pro-oxidant-antioxidant balance in the treated rats. Increased amounts of products of reactions of lipid peroxidation and exhaustion of the enzymatic antioxidant system in liver, heart and kidney tissues were detected. In general, Les-3288, Les-3833 and Les-3882 compounds exhibited less pro-oxidant action, compared with the effect of doxorubicin. According to the results of influencing the pro-oxidant-antioxidant balance in the selected tissues, the studied compounds can be ranked in the following order: doxorubicin >> Les-3833 > Les-3288 >> Les-3882. The results of measuring direct scavenging ability of these compounds observed in 24 h suggests their lower toxic effect compared with the effect of the doxorubicin. The obtained results are in correspondence with the results of our recent experiments demonstrating their antineoplastic effect in vitro (Kobylinska L. et al., 2016) and anticancer action in vivo (Kobylinska L. et al., 2018), as well as their lower general toxicity in vivo compared with doxorubicin (Kobylinska L. et al., 2014, 2015, 2016).
Impact of N-acetylcysteine on antitumor activity of doxorubicin and landomycin A in NK/Ly lymphoma-bearing mice
Yu. S. Kozak1, R. R. Panchuk2, N. R. Skorokhyd2, L. V. Lehka2, R. S. Stoika1,2
1Ivan Franko National University of Lviv, Ukraine;
2Іnstitute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
e-mail: stoika@cellbiol.lviv.ua
N-acetylcysteine (NAC) is a dietary supplement demonstrating antioxidant and liver protecting effects that is widely used in clinics. NAC is considered to possess potential therapeutic activity for health disorders characterized by generation of free oxygen radicals, as well as potential for decreasing negative side effects of various drugs. However, the mechanisms of such tissue-protective actions of NAC remain poorly understood. The main aim of this work was to study therapeutic effects of NAC applied together with the “gold standard” of chemotherapy doxorubicin (Dx) or the novel experimental drug landomycin A (LA) to mice bearing NK/Ly lymphoma. It was revealed that NAC significantly decreased the nephrotoxicity of Dx (measured as creatinine level), possessed moderate immunomodulating activity (as revealed by an increase in number of cytotoxic T-lymphocytes), and partially increased survival of NK/Ly lymphoma-bearing animals treated with Dx. On the contrary, there was little tissue-protective effect of NAC towards LA due to the weak side effects of this anticancer drug, however, the combined use of NAC and LA significantly increased survival (60+ days) of LA-treated animals with NK/Ly lymphoma. Summarizing, NAC possesses a moderate tissue-protective activity towards Dx action but lacks a major therapeutic effect. However, in the case of LA action, NAC significantly increases its anticancer activity with no impact on its negative side effects. Further studies of the molecular mechanisms underlying that activity of NAC towards the action of LA are in progress.
Evaluation of antiproliferative activity of pyrazolothiazolopyrimidine derivatives
N. S. Finiuk1,2, Yu. V. Ostapiuk2, V. P. Hreniukh2, Ya. R. Shalai2,
V. S. Matiychuk2, M. D. Obushak2, R.S. Stoika1*, A. M. Babsky2**
1Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
2Ivan Franko National University of Lviv, Ukraine;
*e-mail: stoika@cellbiol.lviv.ua; **e-mail: andriy.babsky@lnu.edu.ua
The research aim was to test cytotoxic effects in vitro of seven novel pyrazolothiazolopyrimidine derivatives in targeting several lines of tumor and pseudo-normal mammalian cells. We demonstrated that cytotoxic effects of these derivatives depended on the tissue origin of targeted cells. Leukemia cells were found to be the most sensitive to the action of compounds 2 and 7. Compound 2 demonstrated approximately two times higher toxicity towards the multidrug-resistant sub-line of HL-60/ADR cells compared to the Doxorubicin effect. Antiproliferative action of compounds 2 and 7 dropped in the order: leukemia > melanoma > hepatocarcinoma > glioblastoma > colon carcinoma > breast and ovarian carcinoma cells. These compounds were less toxic than Doxorubicin towards the non-tumor cells. The novel pyrazolothiazolopyrimidine, compound 2, demonstrated high toxicity towards human leukemia and, of special importance, towards multidrug-resistant leukemia cells, and low toxicity towards pseudo-normal cells.
Antioxidative effect of the N-stearoylethanolamine in the heart tissue and blood plasma of rats under doxorubicin treatment
I. A. Goudz, N. M. Gula, T. O. Khmel, T. M. Goridko, A. G. Berdyshev
Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: ngula@biochem.kiev.ua
The influence of N-stearoylethanolamine on the alterated antioxidant enzyme activity in the heart tissue and blood plasma of rats under the doxorubicin treatment was investigated. It was shown that doxorubicin administration caused the decrease of antioxidant enzymes activity (superoxide dismutase and glutathione peroxidase) in the heart tissue. Administration of the NSE promoted the partial normalization of these enzymes activity. It was shown that doxorubicin treatment caused the increase of the urea and creatinine level in the blood plasma of experimental animals. The NSE administration normalized the level of the urea and did not affect creatinine level.
Modulation of temozolomide action towards rat and human glioblastoma cells in vitro by its combination with doxorubicin and immobilization with nanoscale polymeric carrier
N. S. Finiuk1, J. V. Senkiv1, A. O. Riabtseva2,
N. Y. Mitina2, N. I. Molochii1, M. O. Kitsera1,
S. S. Avdieiev3, O. S. Zaichenko2, R. S. Stoika1
1Institute of Cell Biology, National Academy of Science of Ukraine, Lviv;
2Lviv National Polytechnic University, Ukraine;
3Institute of Molecular Biology and Genetics, National Academy
of Science of Ukraine, Ukraine;
е-mail: stoika@cellbiol.lviv.ua
Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) occur more frequently than other types of primary central nervous system tumors, having a combined incidence of 5–8/100,000 population. Even with aggressive treatment using surgery, radiation, and chemotherapy, median reported survival is less than one year. Alkylating agents, such as temozolomide (TMZ), are among the most effective cytotoxic agents used for malignant gliomas, however, the responses still remain poor. Here, we present data about an enhancement of TMZ treatment effect towards rat and human glioma cells in vitro by immobilizing this drug with a new nanoscale polymeric-phospholipidic delivery system. It is a water-soluble comb-like poly(PM-co-GMA)-graft-PEG polymer consisting of a backbone that is a copolymer of 5-tert-butyl-peroxy-5-methyl-l-hexene-3-yne (PM) and glycidyl methacrylate (GMA) and polyethylene glycol (PEG) side chains. The molecular weight of the carrier was 94,000 g/mol. Conjugation of TMZ with a novel polymeric carrier functionalized with phosphatidylcholine resulted in approximately 2 times enhancement of anticancer activity of TMZ. Combining of TMZ with doxorubicin (50 nM) resulted in further enhancement by 23% of the anti-proliferative effect of TMZ. TMZ caused apoptosis in glioma cells via activation of MAPK signaling pathway, inhibition of STAT3, and affected a transition through G2/M phase of cell cycle. These features make the novel nano-formulation of TMZ a perspective strategy for further development of this drug.