Synergism of three-drug combinations of sanguinarine and other plant secondary metabolites with digitonin and doxorubicin in multi-drug resistant cancer cells

Phytomedicine ◽  
2012 ◽  
Vol 19 (14) ◽  
pp. 1288-1297 ◽  
Author(s):  
Safaa Yehia Eid ◽  
Mahmoud Zaki El-Readi ◽  
Michael Wink
Keyword(s):  
Secondary Metabolites ◽  
Cancer Cells ◽  
Plant Secondary Metabolites ◽  
Drug Combinations ◽  
Drug Resistant

Digitonin synergistically enhances the cytotoxicity of plant secondary metabolites in cancer cells

Phytomedicine ◽  
2012 ◽  
Vol 19 (14) ◽  
pp. 1307-1314 ◽  
Author(s):  
Safaa Yehia Eid ◽  
Mahmoud Zaki El-Readi ◽  
Michael Wink
Keyword(s):  
Secondary Metabolites ◽  
Cancer Cells ◽  
Plant Secondary Metabolites

scholarly journals The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1094
Author(s):  
Jin Xu ◽  
Xi Yang ◽  
Dhanraj Deshmukh ◽  
Hegang Chen ◽  
Shengyun Fang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Cell Lines ◽  
Drug Combinations ◽  
Drug Resistant ◽  
Prostate Cancer Cells ◽  
Feedforward Loop ◽  
Underlying Mechanisms

Background: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and the underlying mechanisms are yet to be fully explored. Aim and methods: The aim of this study is to investigate drug combinations that inhibit the growth of drug-resistant cells and determine the underlying mechanisms of their actions. In addition, we also established cell lines that are resistant to combination treatments and tested new compounds to overcome the phenomenon of double drug-resistance. Results: Our results show that the combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibit the growth of prostate cancer cells that are resistant to either drug alone. The downregulation of transcription factor E2F1 plays a crucial role in cellular inhibition in response to the combined therapy. Notably, we found that the androgen receptor (AR) variant AR3 (a.k.a. AR-V7), but not AR full length (AR-FL), positively regulates E2F1 expression in these cells. E2F1 in turn regulates AR3 and forms a positive regulatory feedforward loop. We also established double drug-resistant cell lines that are resistant to ENZ+DTX combination therapy and found that the expression of both AR3 and E2F1 was restored in these cells. Furthermore, we identified that auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, overcame drug resistance and inhibited the growth of drug-resistant prostate cancer cells both in vitro and in vivo. Conclusion and significance: This proof-of-principle study demonstrates that targeting the E2F1/AR3 feedforward loop via a combination therapy or a multi-targeting drug could circumvent castration resistance in prostate cancer.

scholarly journals Multiple Molecular Mechanisms to Overcome Multidrug Resistance in Cancer by Natural Secondary Metabolites

2021 ◽  
Vol 12 ◽  
Author(s):  
Mahmoud Zaki El-Readi ◽  
Ahmed M. Al-Abd ◽  
Mohammad A. Althubiti ◽  
Riyad A. Almaimani ◽  
Hiba Saeed Al-Amoodi ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Secondary Metabolites ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Plant Secondary Metabolites ◽  
Cell Growth Inhibition ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Drug Concentrations ◽  
Pharmaceutical Agents

Plant secondary metabolites (SMs) common natural occurrences and the significantly lower toxicities of many SM have led to the approaching development and use of these compounds as effective pharmaceutical agents; especially in cancer therapy. A combination of two or three of plant secondary metabolites together or of one SM with specific anticancer drugs, may synergistically decrease the doses needed, widen the chemotherapeutic window, mediate more effective cell growth inhibition, and avoid the side effects of high drug concentrations. In mixtures they can exert additive or even synergistic activities. Many SM can effectively increase the sensitivity of cancer cells to chemotherapy. In phytotherapy, secondary metabolites (SM) of medicinal plants can interact with single or multiple targets. The multi-molecular mechanisms of plant secondary metabolites to overcome multidrug resistance (MDR) are highlighted in this review. These mechanisms include interaction with membrane proteins such as P-glycoprotein (P-gp/MDR1); an ATP-binding cassette (ABC) transporter, nucleic acids (DNA, RNA), and induction of apoptosis. P-gp plays an important role in the development of MDR in cancer cells and is involved in potential chemotherapy failure. Therefore, the ingestion of dietary supplements, food or beverages containing secondary metabolites e.g., polyphenols or terpenoids may alter the bioavailability, therapeutic efficacy and safety of the drugs that are P-gp substrates.

Caffeoylquinic Acids with Potential Biological Activity from Plant In vitro Cultures as Alternative Sources of Valuable Natural Products

2020 ◽  
Vol 26 (24) ◽  
pp. 2817-2842
Author(s):  
Ewa Skała ◽  
Joanna Makowczyńska ◽  
Joanna Wieczfinska ◽  
Tomasz Kowalczyk ◽  
Przemysław Sitarek
Keyword(s):  
Secondary Metabolites ◽  
Cell Suspension ◽  
Plant Species ◽  
Plant Secondary Metabolites ◽  
Cell Suspension Cultures ◽  
In Vitro Cultures ◽  
Transformed Roots ◽  
Transgenic Roots ◽  
Plant In Vitro Cultures

Background: For a long time, the researchers have been looking for new efficient methods to enhance production and obtain valuable plant secondary metabolites, which would contribute to the protection of the natural environment through the preservation of various plant species, often rare and endangered. These possibilities offer plant in vitro cultures which can be performed under strictly-controlled conditions, regardless of the season or climate and environmental factors. Biotechnological methods are promising strategies for obtaining the valuable plant secondary metabolites with various classes of chemical compounds including caffeoylquinic acids (CQAs) and their derivatives. CQAs have been found in many plant species which are components in the daily diet and exhibit a wide spectrum of biological activities, including antioxidant, immunomodulatory, antihypertensive, analgesic, anti-inflammatory, hepato- and neuroprotective, anti-hyperglycemic, anticancer, antiviral and antimicrobial activities. They have also been found to offer protection against Alzheimer’s disease, and play a role in weight reduction and lipid metabolism control, as well as modulating the activity of glucose-6-phosphatase involved in glucose metabolism. Methods: This work presents the review of the recent advances in use in vitro cultures of various plant species for the alternative system to the production of CQAs and their derivatives. Production of the secondary metabolites in in vitro culture is usually performed with cell suspension or organ cultures, such as shoots and adventitious or transformed roots. To achieve high production of valuable secondary metabolites in in vitro cultures, the optimization of the culture condition is necessary with respect to both biomass accumulation and metabolite content. The optimization of the culture conditions can be achieved by choosing the type of medium, growth regulators or growth conditions, selection of high-productivity lines or culture period, supplementation of the culture medium with precursors or elicitor treatments. Cultivation for large-scale in bioreactors and genetic engineering: Agrobacterium rhizogenes transformation and expression improvement of transcriptional factor or genes involved in the secondary metabolite production pathway are also efficient strategies for enhancement of the valuable secondary metabolites. Results: Many studies have been reported to obtain highly productive plant in vitro cultures with respect to CQAs. Among these valuable secondary metabolites, the most abundant compound accumulated in in vitro cultures was 5-CQA (chlorogenic acid). Highly productive cultures with respect to this phenolic acid were Leonurus sibiricus AtPAP1 transgenic roots, Lonicera macranthoides and Eucomia ulmoides cell suspension cultures which accumulated above 20 mg g-1 DW 5-CQA. It is known that di- and triCQAs are less common in plants than monoCQAs, but it was also possible to obtain them by biotechnological methods. Conclusion: The results indicate that the various in vitro cultures of different plant species can be a profitable approach for the production of CQAs. In particular, an efficient production of these valuable compounds is possible by Lonicera macranthoides and Eucomia ulmoides cell suspension cultures, Leonurus sibiricus transformed roots and AtPAP1 transgenic roots, Echinacea angustifolia adventitious shoots, Rhaponticum carthamoides transformed plants, Lavandula viridis shoots, Sausera involucrata cell suspension and Cichorium intybus transformed roots.

Plant Secondary Metabolites in Cancer Chemotherapy: Where are We?

2012 ◽  
Vol 13 (5) ◽  
pp. 632-650 ◽  
Author(s):  
David M. Pereira ◽  
Patricia Valentao ◽  
Georgina Correia-da-Silva ◽  
Natercia Teixeira ◽  
Paula B. Andrade
Keyword(s):  
Secondary Metabolites ◽  
Cancer Chemotherapy ◽  
Plant Secondary Metabolites
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