scholarly journals Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 251
Author(s):  
Anida Hasanovic ◽  
Méliné Simsir ◽  
Frank S. Choveau ◽  
Enzo Lalli ◽  
Isabelle Mus-Veteau
Keyword(s):  
Adrenocortical Carcinoma ◽  
Standard Treatment ◽  
Treatment Effectiveness ◽  
Therapeutic Option ◽  
Treatment Resistance ◽  
Proton Motive Force ◽  
Carcinoma Cells ◽  
Drug Efflux ◽  
Multidrug Transporters ◽  
Risk Of Relapse

Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We recently showed that the Hedgehog receptor Patched is expressed in ACC, where it strongly contributes to doxorubicin efflux and treatment resistance. Here, we report the identification of a new inhibitor of Patched drug efflux, the anti-histaminergic drug astemizole. We show that astemizole enhances the cytotoxic, proapoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells at concentrations of astemizole or doxorubicin that are not effective by themselves. Our results suggest that a low concentration of astemizole sensitizes ACC cells to doxorubicin, which is a component of the standard treatment for ACC composed of etoposide, doxorubicin, cisplatin and mitotane (EDPM). Patched uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that the use of astemizole or a derivative in combination with EDPM could be a promising therapeutic option for ACC by increasing the treatment effectiveness at lower doses of EDPM, which would reduce the severe side effects of this regimen.

scholarly journals Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1500 ◽  
Author(s):  
Laurie Signetti ◽  
Nelli Elizarov ◽  
Méliné Simsir ◽  
Agnès Paquet ◽  
Dominique Douguet ◽  
...  
Keyword(s):  
Proton Motive Force ◽  
Multidrug Transporter ◽  
Drug Efflux ◽  
Brafv600e Mutation ◽  
Multidrug Transporters ◽  
Xenograft Models ◽  
Melanoma Patients ◽  
Almost All ◽  
Sar Study ◽  
Human Xenograft Models

Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAFV600E melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAFV600E melanoma.

scholarly journals Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency

Cells ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 107 ◽  
Author(s):  
Anida Hasanovic ◽  
Isabelle Mus-Veteau
Keyword(s):  
Cancer Cells ◽  
Abc Transporters ◽  
Adrenocortical Carcinoma ◽  
Efflux Pump ◽  
Therapeutic Option ◽  
Chemotherapy Resistance ◽  
Chemotherapeutic Agents ◽  
Multidrug Transporter ◽  
Drug Efflux

One of the crucial challenges in the clinical management of cancer is resistance to chemotherapeutics. Multidrug resistance (MDR) has been intensively studied, and one of the most prominent mechanisms underlying MDR is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. Despite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and thereby increase classical chemotherapy efficacy, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitors due to toxicity issues. Hedgehog signaling is aberrantly activated in many cancers, and has been shown to be involved in chemotherapy resistance. Recent studies showed that the Hedgehog receptor Ptch1, which is over-expressed in many recurrent and metastatic cancers, is a multidrug transporter and it contributes to the efflux of chemotherapeutic agents such as doxorubicin, and to chemotherapy resistance. Remarkably, Ptch1 uses the proton motive force to efflux drugs, in contrast to ABC transporters, which use ATP hydrolysis. Indeed, the “reversed pH gradient” that characterizes cancer cells, allows Ptch1 to function as an efflux pump specifically in cancer cells. This makes Ptch1 a particularly attractive therapeutic target for cancers expressing Ptch1, such as lung, breast, prostate, ovary, colon, brain, adrenocortical carcinoma, and melanoma. Screening of chemical libraries have identified several molecules that are able to enhance the cytotoxic effect of different chemotherapeutic agents by inhibiting Ptch1 drug efflux activity in different cancer cell lines that endogenously over-express Ptch1. In vivo proof of concept has been performed in mice where combining one of these compounds with doxorubicin prevented the development of xenografted adrenocortical carcinoma tumors more efficiently than doxorubicin alone, and without obvious undesirable side effects. Therefore, the use of a Ptch1 drug efflux inhibitor in combination with classical or targeted therapy could be a promising therapeutic option for Ptch1-expressing cancers.

scholarly journals Cellular and Molecular Aspects of Anti-Melanoma Effect of Minocycline—A Study of Cytotoxicity and Apoptosis on Human Melanotic Melanoma Cells

2020 ◽  
Vol 21 (18) ◽  
pp. 6917
Author(s):  
Jakub Rok ◽  
Zuzanna Rzepka ◽  
Artur Beberok ◽  
Justyna Pawlik ◽  
Dorota Wrześniok
Keyword(s):  
Myeloid Leukemia ◽  
Standard Treatment ◽  
Annexin V ◽  
Medical Problem ◽  
Melanoma Cells ◽  
Carcinoma Cells ◽  
Anti Cancer ◽  
Acute Myeloid Leukemia Cells ◽  
Molecular Aspects ◽  
Therapy Result

Minocycline is a tetracycline compound with pleiotropic pharmacological properties. In addition to its antibacterial action, it shows many non-antimicrobial effects, including an anti-cancer activity. The anti-cancer action was confirmed in studies on ovarian carcinoma cells, hepatocellular carcinoma cells, glioma cells, or acute myeloid leukemia cells. Malignant melanoma remains a serious medical problem despite the extensive knowledge of the disease. The low effectiveness of the standard treatment, as well as the resistance to therapy, result in high mortality rates. This work aimed to investigate the potential and mechanisms of anti-melanoma action of minocycline. Human skin melanotic melanoma cell line COLO 829 was used in the study. The obtained results showed that minocycline decreased cell viability and inhibited the growth of melanoma cells, proportional to the drug concentration as well as to the time of incubation. The EC50 values were calculated to be 78.6 µM, 31.7 µM, and 13.9 µM for 24 h, 48 h, and 72 h, respectively. It was observed that treated cells had a disturbed cell cycle and significantly changed morphology. Moreover, minocycline caused a decrease in mitochondrial membrane potential and an increase in cells with a low level of reduced thiols. Finally, it was found that the anti-melanoma effect of minocycline was related to the induction of apoptosis. The drug activated caspases 8, 9, and 3/7 as well as increased the number of annexin V-positive cells. The presented results show that minocycline possesses anti-melanoma potential.

scholarly journals Tocilizumab Improves the Prognosis of COVID-19 in Patients with High IL-6

2021 ◽  
Vol 10 (8) ◽  
pp. 1583
Author(s):  
Robert Flisiak ◽  
Jerzy Jaroszewicz ◽  
Magdalena Rogalska ◽  
Tadeusz Łapiński ◽  
Aleksandra Berkan-Kawińska ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Mechanical Ventilation ◽  
Confidence Interval ◽  
Clinical Improvement ◽  
Interleukin 6 ◽  
Death Rate ◽  
Treatment Effectiveness ◽  
Therapeutic Option ◽  
Oxygen Supplementation ◽  
End Points

Despite direct viral effect, the pathogenesis of coronavirus disease 2019 (COVID-19) includes an overproduction of cytokines including interleukin 6 (IL-6). Therefore, tocilizumab (TOC), a monoclonal antibody against IL-6 receptors, was considered as a possible therapeutic option. Patients were selected from the SARSTer database, containing 2332 individuals with COVID-19. Current study included 825 adult patients with moderate to severe course. Analysis was performed in 170 patients treated with TOC and 655 with an alternative medication. The end-points of treatment effectiveness were death rate, need for mechanical ventilation, and clinical improvement. Patients treated with TOC were balanced compared to non-TOC regarding gender, age, BMI, and prevalence of coexisting conditions. Significant effect of TOC on death was demonstrated in patients with baseline IL-6 > 100 pg/mL (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.08–0.57). The best effectiveness of TOC was achieved in patients with a combination of baseline IL-6 > 100 pg/mL and either SpO2 ≤ 90% (HR: 0.07) or requiring oxygen supplementation (HR: 0.18). Tocilizumab administration in COVID-19 reduces mortality and speeds up clinical improvement in patients with a baseline concentration of IL-6 > 100 pg/mL, particularly if they need oxygen supplementation owing to the lower value of SpO2 ≤ 90%.

A Case of Myxoid Adrenocortical Carcinoma With Extensive Lipomatous Metaplasia

2003 ◽  
Vol 127 (2) ◽  
pp. 227-230 ◽  
Author(s):  
Miki Izumi ◽  
Hiromi Serizawa ◽  
Keiichi Iwaya ◽  
Kazuhiro Takeda ◽  
Hironobu Sasano ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenocortical Carcinoma ◽  
Adrenal Tumor ◽  
Carcinoma Cells ◽  
Peculiar Feature ◽  
Radiographic Examination ◽  
Rare Phenomenon ◽  
Cut Surface ◽  
Vacuolated Cytoplasm ◽  
Lipomatous Metaplasia

Abstract We report a combination of unusual myxoid change and extensive lipomatous metaplasia of an adrenocortical carcinoma. The patient was a 38-year-old man with hypertension and heart failure. Radiographic examination revealed the presence of a left adrenal tumor, and adrenalectomy was performed. The tumor weighed 380 g and appeared encapsulated. The cut surface was predominantly gelatinous. Histologically, the tumor was composed of atypical round cells with eosinophilic to vacuolated cytoplasm. The tumor was diagnosed as adrenocortical carcinoma. The stroma accumulated copious mucinous material. In addition, individual to nodular mature adipocytes were admixed throughout the tumor. The transition from carcinoma cells to mature adipocytes was recognized. Myxoid change is a very rare phenomenon in adrenocortical carcinoma, and only 10 similar cases have been reported to date. Lipomatous metaplasia is another peculiar feature of adrenocortical lesions that has been reported only in benign conditions. To our knowledge, this is the first reported case of adrenocortical carcinoma with lipomatous metaplasia.

scholarly journals How informative are the leukocyte formula and ESR for COVID-19 patients’ monitoring?

2021 ◽  
Vol 73 (2) ◽  
pp. 81-85
Author(s):  
I.M. Arestov ◽  
A.A. Anisochkin ◽  
O.I. Yudakov ◽  
E.A. Sukhareva
Keyword(s):  
Erythrocyte Sedimentation Rate ◽  
Sedimentation Rate ◽  
Blood Test ◽  
Standard Treatment ◽  
Treatment Effectiveness ◽  
Dynamic Monitoring ◽  
Erythrocyte Sedimentation ◽  
Number Of Patients ◽  
Coronavirus Infection ◽  
Wbc Count

To provide dynamic monitoring of the treatment effectiveness in the case of patients with a new coronavirus infection, it is important to consider that simple and illustrative methods are needed. A clinical blood test is the first and mandatory patients’ examination. This article presents the analysis of the leukocyte formula parameters and the erythrocyte sedimentation rate (ESR) in COVID-19 patients before treatment and during the period from the 1st to the 15th day of standard treatment. Therefore, lymphocytopenia, neutrophilosis, and increased ESR were recorded upon the patients’ admission to the hospital. Statistically significant deviations were manifested on the 10th day of treatment in the absolute WBC count increase in the case of existing leukopenia. During treatment, an increase in the number of patients with normal ESR, as well as a decrease in neutrophilosis, leukopenia and lymphopenia was observed, but no statistically significant differences were found.

scholarly journals Differentiation potential to neural-like cells in human adrenocortical carcinoma SW-13 cells

2019 ◽  
Author(s):  
Eriko Shimada ◽  
Yusuke Tsuruwaka
Keyword(s):  
Early Diagnosis ◽  
Adrenal Gland ◽  
Cancer Cells ◽  
Adrenocortical Carcinoma ◽  
Neural Differentiation ◽  
Neural Induction ◽  
Carcinoma Cells ◽  
Rare Cancer ◽  
Differentiation Potential ◽  
Aggressive Tumor

Various cancer cells are known to show neural differentiation. Adrenocortical carcinoma (ACC) is a rare and frequently aggressive tumor originating in the cortex of the adrenal gland. Early diagnosis of ACC is challenging due to a lot of unknown aspects such as cell characteristics in a rare cancer. In the present study, morphological features were examined in the adrenal cortex carcinoma cells SW-13 as an initial candidate, which were exposed to neural differentiation condition. SW-13 cells treated with the neural induction supplement showed neural-like differentiation with elongated filaments. It was suggested that SW-13 cells had neural differentiation potential and could be a research tool to elucidate the cell characteristics in future ACC studies.

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