scholarly journals Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1867
Author(s):  
Nelly Durand ◽  
Méliné Simsir ◽  
Laurie Signetti ◽  
Fabien Labbal ◽  
Robert Ballotti ◽  
...  
Keyword(s):  
Melanoma Cells ◽  
Carcinoma Cells ◽  
Drug Efflux ◽  
Cancer Treatments ◽  
Anti Cancer ◽  
Efflux Inhibition ◽  
Melanoma Patients ◽  
Almost All ◽  
Chemotherapy Efficacy ◽  
Cells Death

We previously reported that methiothepin, a small molecule known as a nonselective serotonin 5-HT receptor antagonist, inhibited the doxorubicin efflux activity of the Hedgehog receptor Ptch1 and enhanced the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on adrenocortical carcinoma cells. Here, we show that methiothepin also inhibits doxorubicin efflux and increases doxorubicin cytotoxicity in melanoma cells which endogenously overexpress Ptch1. Melanoma patients having the BRAFV600E mutation are treated with vemurafenib, an inhibitor of BRAFV600E, often in combination with trametinib, an inhibitor of MEK. Almost all patients ultimately acquire resistance to the treatment leading to disease progression. Here, we report that methiothepin overcomes the resistance of BRAFV600E melanoma cells by enhancing the cytotoxicity of vemurafenib and trametinib on these cells leading to melanoma cells death. We observe that the addition of methiothepin to vemurafenib prevents migration of resistant melanoma cells more efficiently than vemurafenib alone. Our results provide an additional proof that Ptch1 drug efflux inhibition increases the effectiveness of anti-cancer treatments and overcomes resistance of melanoma cells expressing Ptch1.

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 Regulation of signal transduction pathways in colorectal cancer: implications for therapeutic resistance

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12338
Author(s):  
Yeelon Yeoh ◽  
Teck Yew Low ◽  
Nadiah Abu ◽  
Pey Yee Lee
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Abc Transporters ◽  
Advanced Colorectal Cancer ◽  
Drug Efflux ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Anti Cancer ◽  
Notch Pathways ◽  
Spectrum Of Patients

Resistance to anti-cancer treatments is a critical and widespread health issue that has brought serious impacts on lives, the economy and public policies. Mounting research has suggested that a selected spectrum of patients with advanced colorectal cancer (CRC) tend to respond poorly to both chemotherapeutic and targeted therapeutic regimens. Drug resistance in tumours can occur in an intrinsic or acquired manner, rendering cancer cells insensitive to the treatment of anti-cancer therapies. Multiple factors have been associated with drug resistance. The most well-established factors are the emergence of cancer stem cell-like properties and overexpression of ABC transporters that mediate drug efflux. Besides, there is emerging evidence that signalling pathways that modulate cell survival and drug metabolism play major roles in the maintenance of multidrug resistance in CRC. This article reviews drug resistance in CRC as a result of alterations in the MAPK, PI3K/PKB, Wnt/β-catenin and Notch pathways.

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 KPNB1 Inhibitor Importazole Reduces Ionizing Radiation-Increased Cell Surface PD-L1 Expression by Modulating Expression and Nuclear Import of IRF1

2021 ◽  
Vol 43 (1) ◽  
pp. 153-162
Author(s):  
Hironori Yoshino ◽  
Yoshiaki Sato ◽  
Manabu Nakano
Keyword(s):  
Cell Surface ◽  
Western Blot ◽  
Nuclear Import ◽  
Carcinoma Cells ◽  
Cancer Treatments ◽  
Interferon Regulatory Factor 1 ◽  
Programmed Death ◽  
Anti Cancer ◽  
Checkpoint Molecule ◽  
Transport Receptor

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that negatively regulates anti-tumor immunity. Recent reports indicate that anti-cancer treatments, such as radiation therapy, increase PD-L1 expression on the surface of tumor cells. We previously reported that the nuclear transport receptor karyopherin-β1 (KPNB1) is involved in radiation-increased PD-L1 expression on head-and-neck squamous cell carcinoma cells. However, the mechanisms underlying KPNB1-mediated, radiation-increased PD-L1 expression remain unknown. Thus, the mechanisms of radiation-increased, KPNB1-mediated PD-L1 expression were investigated by focusing on the transcription factor interferon regulatory factor 1 (IRF1), which is reported to regulate PD-L1 expression. Western blot analysis showed that radiation increased IRF1 expression. In addition, flow cytometry showed that IRF1 knockdown decreased cell surface PD-L1 expression of irradiated cells but had a limited effect on non-irradiated cells. These findings suggest that the upregulation of IRF1 after irradiation is required for radiation-increased PD-L1 expression. Notably, immunofluorescence and western blot analyses revealed that KPNB1 inhibitor importazole not only diffused nuclear localization of IRF1 but also decreased IRF1 upregulation by irradiation, which attenuated radiation-increased PD-L1 expression. Taken together, these findings suggest that KPNB1 mediates radiation-increased cell surface PD-L1 expression through both upregulation and nuclear import of IRF1.

271 MIR-221/MDM2/P53 CONTROL LOOP SENSITIZES HEPATOCELLULAR CARCINOMA CELLS TO ANTI-CANCER TREATMENTS

2012 ◽  
Vol 56 ◽  
pp. S113
Author(s):  
F. Fornari ◽  
M. Milazzo ◽  
C. Giovannini ◽  
M. Galassi ◽  
M. Negrini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Carcinoma Cells ◽  
Control Loop ◽  
Cancer Treatments ◽  
Hepatocellular Carcinoma Cells ◽  
Anti Cancer

Use of Homeopathy in Integrative Oncology in Strasbourg, France: Multi-center Cross-Sectional Descriptive Study of Patients Undergoing Cancer Treatment

Homeopathy ◽  
2021 ◽  
Author(s):  
J-L Bagot ◽  
Adeline Legrand ◽  
Ingrid Theunissen
Keyword(s):  
General Practitioner ◽  
Side Effects ◽  
Descriptive Study ◽  
Integrative Oncology ◽  
Cancer Treatments ◽  
Cross Sectional ◽  
Cancer Centers ◽  
Anti Cancer ◽  
Loss Of Libido ◽  
Almost All

Abstract Context The use of homeopathy in oncological supportive care seems to be progressing. The first French prevalence study, performed in 2005 in Strasbourg, showed that only 17% of the subjects were using it. What is the situation 12 years later? Materials and Methods This is a descriptive study, using a questionnaire identical to that used in 2005, on 633 patients undergoing treatment in three anti-cancer centers in Strasbourg. The results of the “homeopathy” sub-group were extracted and studied. Results Of the 535 patients included, 164 used homeopathy: that is 30.7%. The main purpose of its use was to reduce the side effects of cancer treatments (75%). Among the users, 82.6% were “somewhat” or “very” satisfied, against “quite” satisfied for 15.5%, and “not at all” satisfied for 1.9%. The homeopathic treatment was prescribed by a doctor in 75.6% of the cases; the general practitioner was kept informed in 87% of the cases and the oncologist in 82%. Fatigue, pain, nausea, anxiety, sadness and diarrhea were improved in 80% of the cases. However, alopecia, weight disorders and loss of libido were the least improved symptoms. The use of homeopathy was significantly associated with the female sex. Conclusion With a prevalence of 30.7%, homeopathy is the most used complementary medicine in integrative oncology in Strasbourg. Over 12 years, we have witnessed an increase of 83% in its use in the same city. Almost all respondents declare themselves satisfied and tell their doctors more readily than in 2005.

T-10 MiR-221/Mdm2/p53 control loop sensitizes hepatocellular carcinoma cells to anti-cancer treatments

2012 ◽  
Vol 44 ◽  
pp. S17
Author(s):  
F. Fornari ◽  
M. Milazzo ◽  
C. Giovannini ◽  
M. Galassi ◽  
M. Negrini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Carcinoma Cells ◽  
Control Loop ◽  
Cancer Treatments ◽  
Hepatocellular Carcinoma Cells ◽  
Anti Cancer

Cancer Treatment with Liposomes Based Drugs and Genes Co-delivery Systems

2018 ◽  
Vol 25 (28) ◽  
pp. 3319-3332 ◽  
Author(s):  
Chuanmin Zhang ◽  
Shubiao Zhang ◽  
Defu Zhi ◽  
Jingnan Cui
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Resistance Mechanisms ◽  
Delivery Systems ◽  
Cell Cycle Checkpoints ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
Cancer Models ◽  
Anti Cancer

There are several mechanisms by which cancer cells develop resistance to treatments, including increasing anti-apoptosis, increasing drug efflux, inducing angiogenesis, enhancing DNA repair and altering cell cycle checkpoints. The drugs are hard to reach curative effects due to these resistance mechanisms. It has been suggested that liposomes based co-delivery systems, which can deliver drugs and genes to the same tumor cells and exhibit synergistic anti-cancer effects, could be used to overcome the resistance of cancer cells. As the co-delivery systems could simultaneously block two or more pathways, this might promote the death of cancer cells by sensitizing cells to death stimuli. This article provides a brief review on the liposomes based co-delivery systems to overcome cancer resistance by the synergistic effects of drugs and genes. Particularly, the synergistic effects of combinatorial anticancer drugs and genes in various cancer models employing multifunctional liposomes based co-delivery systems have been discussed. This review also gives new insights into the challenges of liposomes based co-delivery systems in the field of cancer therapy, by which we hope to provide some suggestions on the development of liposomes based co-delivery systems.

Future Oncotargets: Targeting Overexpressed Conserved Protein Targets in Androgen Independent Prostate Cancer Cell Lines

2020 ◽  
Vol 20 (8) ◽  
pp. 1017-1027
Author(s):  
Abdul M. Baig ◽  
Zohaib Rana ◽  
Mohammad M. Mannan ◽  
Areeba Khaleeq ◽  
Fizza Nazim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Drug Efflux ◽  
Adapter Proteins ◽  
Cancer Drugs ◽  
Protein Targets ◽  
Anti Cancer ◽  
Drug Efflux Pumps ◽  
Cancer Agent ◽  
Androgen Independent

Background: Targeting evolutionarily conserved proteins in malignant cells and the adapter proteins involved in signalling that generates from such proteins may play a cardinal role in the selection of anti-cancer drugs. Drugs targeting these proteins could be of importance in developing anti-cancer drugs. Objectives: We inferred that drugs like loperamide and promethazine that act as antagonists of proteins conserved in cancer cells like voltage-gated Calcium channels (Cav), Calmodulin (CaM) and drug efflux (ABCB1) pump may have the potential to be re-purposed as an anti-cancer agent in Prostate Cancer (PCa). Methods: Growth and cytotoxic assays were performed by selecting loperamide and promethazine to target Cav, CaM and drug efflux (ABCB1) pumps to elucidate their effects on androgen-independent PC3 and DU145 PCa cell lines. Results: We show that loperamide and promethazine in doses of 80-100μg/ml exert oncocidal effects when tested in DU145 and PC3 cell lines. Diphenhydramine, which shares its targets with promethazine, except the CaM, failed to exhibit oncocidal effects. Conclusion: Anti-cancer effects can be of significance if structural analogues of loperamide and promethazine that specifically target Cav, CaM and ABCB1 drug efflux pumps can be synthesized, or these two drugs could be re-purposed after human trials in PCa.

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