Synergy, Additivity and Antagonism between Esculetin and Six Commonly Used Chemotherapeutics in Various Malignant Melanoma Cell Lines—An Isobolographic Analysis

(1) Malignant melanomas are dangerous skin cancers, and the treatment of melanomas with various cytostatic drugs often causes side effects and after their prolonged use resistance to these drugs appears. The aim of this study was to evaluate the anticancer effects of esculetin (a simple coumarin) and to assess pharmacodynamic interactions between esculetin and six commonly used cytostatic drugs (cisplatin, epirubicin, docetaxel, paclitaxel, mitoxantrone and vemurafenib) using an isobolographic analysis. (2) The experiments were carried out on four human malignant melanoma cell lines (FM55P, A375, FM55M2 and SK-MEL28). The effects of esculetin on viability, cell proliferation and cytotoxicity were verified in the range of concentrations of 2–200 μM. (3) Esculetin inhibited, in a dose-dependent manner, malignant melanoma cell viability and proliferation. The IC50 for esculetin ranged from 18.20 ± 2.93 to 120.64 ± 30.39 μM depending on the melanoma cell lines used. The combinations of esculetin with epirubicin and vemurafenib showed antagonistic interactions, the combinations of esculetin with cisplatin, docetaxel and paclitaxel showed additive interactions. For the combinations of esculetin with mitoxantrone, the isobolographic analysis displayed synergy. (4) In the treatment of malignant melanoma, esculetin should not be combined with epirubicin or vemurafenib, due to the reduction of their anticancer effects, while the synergistic interactions (esculetin + mitoxantrone) deserve a preclinical recommendation as a beneficial combination during anticancer therapy

Daphnetin, a Coumarin with Anticancer Potential against Human Melanoma: In Vitro Study of Its Effective Combination with Selected Cytostatic Drugs

(1) The treatment of metastatic or drug-resistant melanoma is still a significant therapeutic problem. The aim of this study was to evaluate the anticancer potential of daphnetin (7,8-dihydroxycoumarin) and its combinations with five different cytostatic drugs (mitoxantrone, docetaxel, vemurafenib, epirubicin and cisplatin). (2) The viability, proliferation and cytotoxicity of daphnetin against four human malignant melanoma cell lines were evaluated. The interactions were assessed using isobolographic analysis for the combinations of daphnetin with each of the five cytostatic drugs. (3) Daphnetin showed anticancer activity against malignant melanoma, with IC50 values ranging from 40.48 ± 10.90 µM to 183.97 ± 18.82 µM, depending on the cell line. The combination of daphnetin with either vemurafenib or epirubicin showed an antagonistic interaction. Moreover, additive interactions were observed for the combinations of daphnetin with cisplatin and docetaxel. The most desirable synergistic interactions for human melanoma metastatic cell lines were observed for the combination of daphnetin with mitoxantrone. (4) The obtained results suggest that daphnetin should not be combined with vemurafenib or epirubicin in the treatment of malignant melanoma due to the abolition of their anticancer effects. The combination of daphnetin with mitoxantrone is beneficial in the treatment of metastatic melanoma due to their synergistic interaction

Znaczenie kannabinoidów w funkcjonowaniu ośrodkowego układu nerwowego

At present, there is a great emphasis of public opinion on the legalisation of medical marijuana, i.e. the top parts of the cannabis plants rich in tetrahydrocannabinol (THC). Nevertheless, in the cannabis plants, there are many various cannabinoids, including cannabidiol (CBD). Scientific reports to-date indicate the possibility for using pharmacologically active cannabinoids in the treatment of such diseases/symptoms as: anorexia, vomiting, neuropathic pain, inflammatory diseases, multiple sclerosis, degenerative diseases of the central nervous system (Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, Tourette’s syndrome), epilepsy, schizophrenia, and obesity. The article presents up-to-date information on the results of experimental studies concerning the effectiveness of cannabinoids, with particular consideration of diseases related with the central nervous system, including epilepsy, neuropathic pain, mental disorders, as well as obesity and anorexia.Aktualnie obserwuje się duży nacisk opinii społecznej na legalizację medycznej marihuany, czyli szczytowych części roślin konopi indyjskich bogatych w tetrahydrokannabinol (THC). Tymczasem, w konopiach jest wiele różnych kannabinoidów, między innymi kannabidiol (CBD). Aktualne doniesienia naukowe wskazują na możliwość wykorzystania farmakologicznej aktywności kannabinoidów w obszarze leczenia takich chorób/ objawów jak: anoreksja, wymioty, ból neurogenny, choroby zapalne, stwardnienie rozsiane, choroby degeneracyjne ośrodkowego układu nerwowego (choroba Parkinsona, Huntingtona, Alzheimera oraz zespół Tourette’a), padaczka, schizofrenia, otyłość. W pracy przedstawiono aktualne informacje na temat wyników prowadzonych dotychczas badań nad skutecznością kannabinoidów, ze szczególnym uwzględnieniem chorób związanych z ośrodkowym układem nerwowym, w tym: padaczką, bólem neuropatycznym, chorobami psychicznymi oraz otyłością i anoreksją

Synergy, Additivity, and Antagonism between Cisplatin and Selected Coumarins in Human Melanoma Cells

(1) Cisplatin (CDDP) is used in melanoma chemotherapy, but it has many side effects. Hence, the search for natural substances that can reduce the dose of CDDP, and CDDP-related toxicity, is highly desired. Coumarins have many biological properties, including anticancer and antiproliferative effects. (2) An in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay on two human melanoma cell lines (FM55P and FM55M2) examined the antitumor properties of CDDP and five naturally occurring coumarins (osthole, xanthotoxin, xanthotoxol, isopimpinellin, and imperatorin). The antiproliferative effects produced by combinations of CDDP with the coumarins were assessed using type I isobolographic analysis. (3) The most potent anticancer properties of coumarins were presented by osthole and xanthotoxol. These compounds were characterized by the lowest median inhibitory concentration (IC50) values relative to the FM55P and FM55M2 melanoma cells. Isobolographic analysis showed that for both melanoma cell lines, the combination of CDDP and osthole exerted synergistic and additive interactions, while the combination of CDDP and xanthotoxol exerted additive interactions. Combinations of CDDP with xanthotoxin, isopimpinellin, and imperatorin showed antagonistic and additive interactions in two melanoma cell lines. (4) The combination of CDDP and osthole was characterized by the most desirable synergistic interaction. Isobolographic analysis allows the selection of potential candidates for cancer drugs among natural substances

Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines—An Isobolographic Analysis

The medical application of cannabidiol (CBD) has been gathering increasing attention in recent years. This non-psychotropic cannabis-derived compound possesses antiepileptic, antipsychotic, anti-inflammatory and anxiolytic properties. Recent studies report that it also exerts antineoplastic effects in multiple types of cancers, including melanoma. In this in vitro study we tried to reveal the anticancer properties of CBD in malignant melanoma cell lines (SK-MEL 28, A375, FM55P and FM55M2) administered alone, as well as in combination with mitoxantrone (MTX) or cisplatin (CDDP). The effects of CBD on the viability of melanoma cells were measured by the MTT assay; cytotoxicity was determined in the LDH test and proliferation in the BrdU test. Moreover, the safety of CBD was tested in human keratinocytes (HaCaT) in LDH and MTT tests. Results indicate that CBD reduces the viability and proliferation of melanoma-malignant cells and exerts additive interactions with MTX. Unfortunately, CBD produced antagonistic interaction when combined with CDDP. CBD does not cause significant cytotoxicity in HaCaT cell line. In conclusion, CBD may be considered as a part of melanoma multi-drug therapy when combined with MTX. A special attention should be paid to the combination of CBD with CDDP due to the antagonistic interaction observed in the studied malignant melanoma cell lines

Additive Interactions between Betulinic Acid and Two Taxanes in In Vitro Tests against Four Human Malignant Melanoma Cell Lines

The incidence of melanoma is steadily increasing worldwide. Melanoma is the most lethal skin cancer, and new therapeutic methods are being sought. Our research aimed to investigate the cytotoxic and antiproliferative effects of betulinic acid in vitro, used alone and in combination with taxanes (paclitaxel, docetaxel) in four melanoma cell lines. Isobolographic analysis allowed us to assess the interactions between these compounds. Betulinic acid had no cytotoxic effect on normal human keratinocyte HaCaT cells; the amount of LDH released by them was significantly lower compared to melanoma cell lines. The present study shows that betulinic acid significantly inhibits the growth of melanoma cell lines in vitro. The IC50 values of betulinic acid ranged from 2.21 µM to 15.94 µM against the four melanoma lines. Co-treatment of betulinic acid with paclitaxel or docetaxel generated desirable drug–drug interactions, such as an additive and additive with a tendency to synergy interactions

Isoquinoline Alkaloids from <i>Coptis chinensis</i> Franch: Focus on Coptisine as a Potential Therapeutic Candidate against Gastric Cancer Cells

Gastric cancer (GC) has high incidence rates and constitutes a common cause of cancer mortality. Despite advances in treatment, GC remains a challenge in cancer therapy which is why novel treatment strategies are needed. The interest in natural compounds has increased significantly in recent years because of their numerous biological activities, including anti-cancer action. The isolation of the bioactive compounds from Coptis chinensis Franch was carried out with the Centrifugal Partition Chromatography (CPC) technique, using a biphasic solvent system composed of chloroform (CHCl3)—methanol (MeOH)—water (H2O) (4:3:3, v/v) with an addition of hydrochloric acid and trietylamine. The identity of the isolated alkaloids was confirmed using a high resolution HPLC-MS chromatograph. The phytochemical constituents of Coptis chinensis such as berberine, jatrorrhizine, palmatine and coptisine significantly inhibited the viability and growth of gastric cancer cell lines ACC-201 and NCI-N87 in a dose-dependent manner, with coptisine showing the highest efficacy as revealed using MTT and BrdU assays, respectively. Flow cytometry analysis confirmed the coptisine-induced population of gastric cancer cells in sub-G1 phase and apoptosis. The combination of coptisine with cisplatin at the fixed-ratio of 1:1 exerted synergistic and additive interactions in ACC-201 and NCI-N87, respectively, as determined by means of isobolographic analysis. In in vivo assay, coptisine was safe for developing zebrafish at the dose equivalent to the highest dose active in vitro, but higher doses (greater than 10 times) caused morphological abnormalities in larvae. Our findings provide a theoretical foundation to further studies on more detailed mechanisms of the bioactive compounds from Coptis chinensis Franch anti-cancer action that inhibit GC cell survival in in vitro settings

Antagonistyczna interakcja lakozamidu z karbamazepiną i walproainianem w modelu drgawek toniczno-klonicznych u myszy

Background. It is estimated that approximately 1% of people worldwide suffer from epilepsy. Currently available antiepileptic drugs (AEDs) are able to control epileptic seizures in about 70% of cases. In the remaining patients (30%), the application of two or three AEDs in combination is necessary for effective seizure management. The goal of this work was to characterize the interaction of three AEDs: lacosamide (LCM), carbamazepine (CBZ) and valproate (VPA) at the fixed-ratio of 1:1:1 in the mouse tonic-clonic seizure model. Material and methods. Male albino Swiss mice, after receiving a combination of LCM, CBZ and VPA, were challenged with electric current to evoke tonic hind limb extension (seizure activity). Protection of the mice from tonic-clonic seizures was assessed by isobolographic analysis to determine the type of interaction occurring between these drugs. Results. Type I isobolographic analysis revealed that the combination of LCM, CBZ and VPA produced infra-additive (antagonistic) interaction in the mouse tonic-clonic seizure model. Conclusions. Since the three-drug mixture of LCM, CBZ and VPA exerted an antagonistic interaction in the tonic-clonic seizure test in mice, we would caution physicians against treating epilepsy patients with this unfavorable combination.Wprowadzenie. Szacuje się, że około 1% osób na całym świecie cierpi na padaczkę. Obecnie dostępne leki przeciwpadaczkowe pozwalają na opanowanie napadów padaczkowych w około 70% przypadków. U pozostałych pacjentów z padaczką (30%) konieczne jest zastosowanie dwóch lub trzech leków przeciwpadaczkowych w kombinacji. Celem pracy było scharakteryzowanie interakcji między trzema lekami przeciwpadaczkowymi: lakozamidem (LCM), karbamazepiną (CBZ) i walproinianem (VPA) w stałym stosunku dawek 1:1:1 w modelu drgawek toniczno-klonicznych u myszy. Materiał i metody. Samce myszy albino Swiss, po otrzymaniu kombinacji LCM, CBZ i VPA, poddano działaniu prądu elektrycznego, aby wywołać toniczny wyprost kończyn tylnych (aktywność drgawkową). Ochronę myszy przed napadami toniczno-klonicznymi oszacowano za pomocą analizy izobolograficznej, aby określić typ interakcji zachodzącej między tymi lekami. Wyniki. Analiza izobolograficzna typu I ujawniła, że kombinacja LCM, CBZ i VPA powodowała oddziaływanie infra-addytywne (antagonistyczne) w modelu drgawek toniczno-klonicznych u myszy. Wnioski. Ponieważ trójlekowa mieszanina LCM, CBZ i VPA wywierała antagonistyczną interakcję w teście napadów toniczno-klonicznych u myszy, specjalne ostrzeżenie jest konieczne dla lekarzy, aby nie leczyć pacjentów z padaczką tą niekorzystną kombinacją

Interactions of retigabine with topiramate in the mouse tonic-clonic seizure model and chimney test - an isobolographic analysis

Introduction and objectives. Nowadays, one of the treatment options for patients with refractory epilepsy is polytherapy with two or more antiepileptic drugs (AEDs). Retigabine (RTG) is a novel third-generation AED with unique molecular mechanisms of action that has recently been approved as an add-on drug for the treatment of tonic-clonic seizures. To characterize types of interactions between RTG and topiramate (TPM – a second-generation AED), the maximal electroshock- induced seizure model (MES) and chimney test in mice were used. Materials and method. In the MES model, the anticonvulsant effects of the drugs in terms of suppression of tonic-clonic seizures in male albino Swiss mice were assessed. In the chimney test, the acute neurotoxic effects of the drugs with respect to impairment of motor coordination were determined. Type I isobolographic analysis for the combination of RTG and TPM was applied to assess the anticonvulsant and neurotoxic effects in both the MES and chimney tests. Total brain concentrations of RTG and TPM were measured to exclude any pharmacokinetic interaction between drugs. Results. The type I isobolographic analysis of interaction revealed that the combination of RTG with TPM produced additive interaction in the MES test and additivity, with a slight tendency towards antagonism in terms of acute neurotoxic effects in the chimney test. Neither RTG nor TPM mutually affected total brain concentrations in the experimental animals. Conclusions. The isobolographically analyzed combination of RTG with TPM is favourable and may be recommended to some patients with refractory epilepsy