Rosmarinic acid is a natural polyphenolic compound that is found in different plant species and used for different medicinal purposes. This study aimed to investigate the chemo-preventive effect of rosmarinic acid and evaluate its antitumor efficacy alone or in combination with Paclitaxel in breast cancer mice model. Ehrlich induced mice mammary solid tumor model was used in the study. Mice were treated with oral rosmarinic acid and intraperitoneal Paclitaxel. Inflammation, angiogenesis, and apoptosis were checked. Enzyme linked immunosorbent assay (ELISA), quantitative real time PCR, and immunohistochemical methods were performed. Rosmarinic acid used prior to tumor induction suppressed NF-κB, TNF-α, vascular endothelial growth factor (VEGF) serum levels, and VEGF receptors. It also triggered apoptosis by restoring the levels of P53, Bcl-2, Bax, and caspase-3. Furthermore, in Ehrlich solid tumor mice, rosmarinic acid, and/or Paclitaxel significantly suppressed tumor growth with an increase in apoptotic markers P53 and Caspase-3 levels, and suppressed the Bcl2/Bax ratio. Rosmarinic acid exerted chemo-preventive and therapeutic potential alone or in combination with Paclitaxel. Moreover, rosmarinic acid targets numerous signaling pathways associated with breast cancer.
- MeSH
- apoptóza účinky léků MeSH
- cinnamáty farmakologie terapeutické užití MeSH
- Ehrlichův tumor farmakoterapie imunologie patologie MeSH
- experimentální nádory MeSH
- kombinovaná farmakoterapie MeSH
- laboratorní zvířata MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádory prsu * farmakoterapie MeSH
- paclitaxel terapeutické užití MeSH
- TNF-alfa účinky léků MeSH
- vaskulární endoteliální růstové faktory účinky léků MeSH
- výsledek terapie MeSH
- Check Tag
- myši MeSH
In this study, twenty-two Amaryllidaceae alkaloids were screened for their anticancer potential. All isolates were evaluated for antiproliferative activities on a panel of 17 human cell types of different tissue origin using WST-1 assay. In addition, we determined the antiproliferative effect with a real-time cell analysis xCELLigence system. Thereafter, to evaluate the barely known in vivo anticancer potential of the most potent molecule haemanthamine, a preliminary study was performed using an Ehrlich tumor-bearing mice model. The results showed that haemanthamine, lycorine and haemanthidine exerted the highest antiproliferative activity. The mean growth percent (GP) value after a single-dose 10 μM treatment was for haemanthamine 21%, for lycorine 21% and for haemanthidine 27% that of untreated control cells (100%). Furthermore, haemanthamine, lycorine and haemanthidine exhibited significant cytotoxicities against all the tested cell lines with individual IC50 values in the micromolar range. Dynamic real-time measures of impedance by xCELLigence indicated that these three compounds suppress cell proliferation after 10 h of treatment at a concentration of 10 μM or higher. Regrettably, in a follow-up in vivo antitumor activity study, haemanthamine showed no statistically significant reduction in the tumor size with no prolongation of survival time of Ehrlich tumor-bearing mice. Taken together, these results provide a new clue and guidance for exploiting Amaryllidaceae alkaloids as anticancer agents.
- MeSH
- alkaloidy chemie farmakologie terapeutické užití MeSH
- Amaryllidaceae chemie metabolismus MeSH
- apoptóza účinky léků MeSH
- Ehrlichův tumor farmakoterapie mortalita patologie MeSH
- fytogenní protinádorové látky chemie farmakologie terapeutické užití MeSH
- Kaplanův-Meierův odhad MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- screeningové testy protinádorových léčiv MeSH
- transplantace heterologní MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIM: To evaluate the anticancer effect of alpha-tomatine (i.p.) either alone or in combination with doxorubicin (i.v.) in a mouse tumour model. METHODS: We studied the effect of repeated alpha-tomatine (0.1 - 9 mg/kg) and/or doxorubicin (2 mg/kg) on the growth and mitotic activity of the solid Ehrlich tumour in vivo, as well as on the survival of the tumour-bearing mice. RESULTS: Monotherapy with alpha-tomatine had a significant dose-dependent anticancer effect which peaked at 1 mg/kg. This was shown by both slowed tumour growth and reduced tumour cell proliferation. We also provide the first evidence that the combination alpha-tomatine (1 mg/kg) and doxorubicin (2 mg/kg) had a synergistic effect and significantly prolonged the survival of the mice. Neither alpha-tomatine nor doxorubicin influenced the infiltration of tumours with CD3+ lymphocytes; nor were we able to find an in vivo modulation of the key molecules of two regulatory pathways reported in vitro as the principal anti-cancer mechanisms of alpha-tomatine, i.e. iNOS and phosphorylated ERK2. However, alpha-tomatine still led to intracellular DNA inhibition and protein synthesis in Ehrlich tumour cells in a short-term culture ex vivo with IC50 values of 8.7 and 6.6 µM. CONCLUSIONS: The results suggest that ΤΟΜ, especially in combination with doxorubicin, may be a promising agent for the treatment of malignant solid tumours. Despite growing knowledge of the mechanisms of ΤΟΜ action in cancer cells, most aspects remain unclear. Parallel organ toxicity, especially potential liver effects, requires careful attention when performing in vivo studies in the future.
- MeSH
- bilirubin krev MeSH
- biologické markery metabolismus MeSH
- doxorubicin aplikace a dávkování MeSH
- Ehrlichův tumor farmakoterapie metabolismus MeSH
- experimentální nádory mléčných žláz farmakoterapie metabolismus MeSH
- játra účinky léků MeSH
- myši MeSH
- proliferace buněk účinky léků MeSH
- protinádorová antibiotika aplikace a dávkování MeSH
- tomatin aplikace a dávkování analogy a deriváty farmakologie MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The limitation of carbonyl reduction represents one possible way to increase the effectiveness of anthracycline doxorubicin (DOX) in cancer cells and decrease its toxicity in normal cells. In vitro, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased the antiproliferative effect of DOX in MCF-7 breast cancer cells. Moreover, ORC significantly decreases DOX toxicity in non-cancerous MCF-10A breast cells and in hepatocytes. The present study was designed to test in mice the in vivo effect of ORC on plasma and tissue concentrations of DOX and its main metabolite DOXOL. The effect of ORC on DOX efficacy in mice bearing solid Ehrlich tumors (EST) was also studied. METHODS: DOX and DOX + ORC combinations were iv administered to healthy mice. Blood samples, livers and hearts were collected during the following 48 h. DOX and DOXOL concentrations were assayed using HPLC. The mice with inoculated EST cells were treated repeatedly iv with DOX and DOX + ORC combinations, and the growth of tumors was monitored. RESULTS: ORC in combination with DOX significantly decreased DOXOL plasma concentrations during four hours after administration, but this significantly affected neither DOX plasma concentrations nor DOX or DOXOL concentrations in the liver and heart at any of intervals tested. In EST bearing mice, ORC did not significantly affect DOX efficacy on tumor growth. However, EST was shown to be an improper model for the testing of ORC efficacy in vivo, as ORC did not inhibit DOXOL formation in EST. ConclusIONS: In vivo, ORC was able to retard DOXOL formation but was not able to improve DOX efficacy in EST-bearing mice.
- MeSH
- doxorubicin analogy a deriváty farmakokinetika farmakologie MeSH
- Ehrlichův tumor farmakoterapie patologie MeSH
- ethanolaminy farmakologie MeSH
- intravenózní podání MeSH
- isochinoliny farmakologie MeSH
- játra metabolismus MeSH
- lékové interakce MeSH
- myokard metabolismus MeSH
- myši MeSH
- protinádorová antibiotika farmakokinetika farmakologie MeSH
- tkáňová distribuce MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Dysfunction of the carnitine system in non-tumour tissue following anticancer therapy has been reported. In this setting, supplementation with carnitine derivatives might increase the general metabolic activity of normal cells so that they might better withstand the adverse effects of chemotherapy aimed at tumour cells. Here we investigated the effect of acetyl-L-carnitine (ALC) alone and in combination with the antineoplastic agent mitoxantrone (MX) in an animal cancer model. METHODS: The effects of MX and MX-ALC were assessed based on gain or loss of body weight and on local growth of a solid form of Ehrlich tumour inoculated into mice. We also performed biochemical analyses like serum activities of some enzymes signalling the functioning of the liver, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Total protein, albumin and bilirubin were also determined in serum. Under favourable conditions, the Ehrlich tumour readily forms metastases, and this is the reason why we performed histological studies of samples of both the liver and heart in order to identify changes that may have mediated the observed effect of the treatment. In addition to those studies, the survival time of treated animals against controls was also noted. RESULTS: MX monotherapy was associated with lower body weight gain, fewer metastases, smaller tumour size, and lower dissemination. ALC alone promoted survival, but had no potentiating effect on MX therapy in terms of survival. Serum biochemistry changes associated with MX-ALC treatment consisted of a significant (p < 0.05) increase in AST with MX at 6 or 9 mg·kg(-1) plus ALC 200 mg·kg(-1) and a significant (p < 0.05) reduction in total protein compared to the corresponding MX group; serum albumin and bilirubin remained unchanged. CONCLUSION: ALC in combination with MX, regardless of the dose of MX, led to higher occurrences of metastases with dissemination to the kidneys, lungs, heart, and mediastinum compared to MX treatment alone. These histological findings indicate that ALC is inappropriate to combine with MX in the treatment of a solid cancer. The protective effect of ALC in combination therapy with the cytostatic drug MX was not supported in this study by our findings that the agent did not improve the therapeutic outcomes of MX therapy.
- MeSH
- acylkarnitin terapeutické užití MeSH
- bilirubin krev MeSH
- Ehrlichův tumor farmakoterapie patologie MeSH
- experimentální nádory jater farmakoterapie patologie MeSH
- mitoxantron terapeutické užití MeSH
- myši MeSH
- protinádorové látky terapeutické užití MeSH
- sérový albumin analýza MeSH
- tělesná hmotnost MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- bleomycin aplikace a dávkování diagnostické užití terapeutické užití MeSH
- Calotropis MeSH
- Ehrlichův tumor farmakoterapie MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- fytoterapie metody využití MeSH
- myši MeSH
- rostlinné extrakty aplikace a dávkování terapeutické užití MeSH
- statistika jako téma MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- klinické zkoušky MeSH
- MeSH
- DNA nádorová účinky léků MeSH
- Ehrlichův tumor farmakoterapie patologie MeSH
- experimentální nádory farmakoterapie patologie MeSH
- myši MeSH
- peritoneální dutina MeSH
- sloučeniny boru farmakologie chemie terapeutické užití MeSH
- transplantace nádorů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
