A New Cytotoxic Dimeric Sesquiterpene Isolated from Inula racemosa Hook. f. (Root): In Vitro and In Silico Analyses

Abstract Background: Our recent investigation directed to synthesize and characterize a novel ruthenium– phloretin complex accompanied by the study of antioxidant in addition to DNA binding capabilities, and to determine the chemotherapeutic activity against breast carcinoma in vitro and in vivo approach.Methods: Ruthenium–phloretin complex was synthesized and characterized using various spectroscopic methods. The complex was further investigated to determine its efficacy in both MCF-7 and MDA-MB-231 human cancer cell lines and finally in an in vivo model of DMBA induced mammary carcinogenesis in ratsResults: Our studies confirm that the chelation of the metal and ligand was materialize by the 3-OH and 9-OH functional groups of the ligand and the complex is found crystalline and was capable of intercalating with CT-DNA. The complex was capable of reducing cellular propagation and initiate apoptotic events in MCF-7 and MDA-MB-231 breast carcinoma cell lines. Additionally, ruthenium-phloretin complex could modulate p53 intervene apoptosis in the breast carcinoma, initiated by the intrinsic apoptotic trail facilitated by the Bcl2 and Bax and at the same time down regulating the PI3K/Akt/mTOR pathway coupled with MMP9 regulated tumor invasive pathways.Conclusions: Ruthenium-phloretin chemotherapy could interrupt, revoke or suspend the succession of breast carcinoma by altering intrinsic apoptosis along with the antiangiogenic pathway, hence fulfilling the role of a prospective candidate in cancer chemotherapeutics in the in the near future.

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A Newfangled Coordinated Ruthenium Phloretin Complex Reprogramming Breast Cancer Microenvironment Interceded by Modulation of PI3K/Akt/Mtor/VEGF Pathway and Modifying The Antioxidant Status Correlated With Intensified Apoptotic Events.

10.21203/rs.3.rs-42460/v1 ◽

2020 ◽

Author(s):

Chenyang He ◽

Junli Wang ◽

Tania Chakraborty ◽

Souvik Roy

Keyword(s):

Breast Carcinoma ◽

Cell Lines ◽

Human Cancer ◽

In Vivo Model ◽

Human Cancer Cell Lines ◽

Vegf Pathway ◽

Breast Carcinoma Cell Lines ◽

Mcf 7

Abstract Background: Our recent investigation directed to synthesize and characterize a novel ruthenium– phloretin complex accompanied by the study of antioxidant in addition to DNA binding capabilities, and to determine the chemotherapeutic activity against breast carcinoma in vitro and in vivo approach.Methods: Ruthenium–phloretin complex was synthesized and characterized using various spectroscopic methods. The complex was further investigated to determine its efficacy in both MCF-7 and MDA-MB-231 human cancer cell lines and finally in an in vivo model of DMBA induced mammary carcinogenesis in ratsResults: Our studies confirm that the chelation of the metal and ligand was materialize by the 3-OH and 9-OH functional groups of the ligand and the complex is found crystalline and was capable of intercalating with CT-DNA. The complex was capable of reducing cellular propagation and initiate apoptotic events in MCF-7 and MDA-MB-231 breast carcinoma cell lines. Additionally, ruthenium-phloretin complex could modulate p53 intervene apoptosis in the breast carcinoma, initiated by the intrinsic apoptotic trail facilitated by the Bcl2 and Bax and at the same time down regulating the PI3K/Akt/mTOR pathway coupled with MMP9 regulated tumor invasive pathways.Conclusions: Ruthenium-phloretin chemotherapy could interrupt, revoke or suspend the succession of breast carcinoma by altering intrinsic apoptosis along with the antiangiogenic pathway, hence fulfilling the role of a prospective candidate in cancer chemotherapeutics in the in the near future.

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Full Structural Characterization of Homoleptic Complexes of Diacetylcurcumin with Mg, Zn, Cu, and Mn: Cisplatin-level Cytotoxicity in Vitro with Minimal Acute Toxicity in Vivo

Molecules ◽

10.3390/molecules24081598 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1598 ◽

Cited By ~ 6

Author(s):

William Meza-Morales ◽

M. Mirian Estévez-Carmona ◽

Yair Alvarez-Ricardo ◽

Marco A. Obregón-Mendoza ◽

Julia Cassani ◽

...

Keyword(s):

Acute Toxicity ◽

Metal Complexes ◽

Single Crystal ◽

Cytotoxic Activity ◽

Therapeutic Potential ◽

Human Cancer ◽

Human Cancer Cell ◽

Human Cancer Cell Lines

At the present time, scientists place a great deal of effort worldwide trying to improve the therapeutic potential of metal complexes of curcumin and curcuminoids. Herein, the synthesis of four homoleptic metal complexes with diacetylcurcumin (DAC), using a ligand designed to prevent the interaction of phenolic groups, rendering metal complexes through the β-diketone functionality, is reported. Due to their physiological relevance, we used bivalent magnesium, zinc, copper, and manganese for complexation with DAC. The resulting products were characterized by ultraviolet-visible (UV-Vis), fluorescence spectroscopy, infrared spectroscopy (IR), liquid and solid-state nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), magnetic moment, mass spectrometry (MS), single crystal, and powder X-ray diffraction (SCXRD and PXRD). Crystallization was achieved in dimethylsulfoxide (DMSO) or N,N-dimethylformamide (DMF) as triclinic systems with space group P-1, showing the metal bound to the β-diketone function, while the 1H-NMR confirmed the preference of the enolic form of the ligand. Single crystal data demonstrated a 1:2 metal:ligand ratio. The inhibition of lipid peroxidation was evaluated using the thiobarbituric acid reactive substance assay (TBARS). All four metal complexes (Mg, Zn, Cu, and Mn) exhibited good antioxidant effect (IC50 = 2.03 ± 0.27, 1.58 ± 0.07, 1.58 ± 0.15 and 1.24 ± 0.10 μM respectively) compared with butylated hydroxytoluene (BHT) and α-tocopherol. The cytotoxic activity in human cancer cell lines against colon adenocarcinoma (HCT-15), mammary adenocarcinoma (MCF-7), and lung adenocarcinoma (SKLU-1) was found comparable ((DAC)2Mg), or ca. 2-fold higher ((DAC)2Zn) than cisplatin. The acute toxicity assays indicate class 5 toxicity, according to the Organization for Economic Co-operation and Development (OECD) guidelines at doses of 3 g/kg for all complexes. No mortality or changes in the behavior of animals in any of the treated groups was observed. A therapeutic potential can be envisaged from the relevant cytotoxic activity upon human cancer cell lines in vitro and the undetected in vivo acute toxicity of these compounds.

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Design, Synthesis, and Molecular Docking Study of Novel Heterocycles Incorporating 1,3,4-Thiadiazole Moiety as Potential Antimicrobial and Anticancer Agents

Molecules ◽

10.3390/molecules24061066 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1066 ◽

Cited By ~ 10

Author(s):

Mohamed El-Naggar ◽

Hanan A. Sallam ◽

Safaa S. Shaban ◽

Salwa S. Abdel-Wahab ◽

Abd El-Galil E. Amr ◽

...

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Anticancer Agents ◽

Human Cancer ◽

Docking Study ◽

Molecular Docking Study ◽

Reference Drug ◽

Human Cancer Cell Lines ◽

Dhfr Inhibitors

A new series of 5-(3,5-dinitrophenyl)-1,3,4-thiadiazole derivatives were prepared and evaluated for their in vitro antimicrobial, antitumor, and DHFR inhibition activity. Compounds 9, 10, 13, and 16 showed strong and broad-spectrum antimicrobial activity comparable to Amoxicillin and Fluconazole as positive antibiotic and antifungal controls, respectively. Compounds 6, 14, and 15 exhibited antitumor activity against four human cancer cell lines, CCRF-CEM leukemia, HCT-15 colon, PC-3 prostate, and UACC-257 melanoma cell lines using Doxorubicin as a reference drug. Compounds 10, 13, 14, and 15 proved to be the most active DHFR inhibitors with an IC50 range of 0.04 ± 0.82–1.00 ± 0.85 µM, in comparison with Methotrexate (IC50 = 0.14 ± 1.38 µM). The highly potent DHFR inhibitors shared a similar molecular docking mode and made a critical hydrogen bond and arene‒arene interactions via Ser59 and Phe31 amino acid residues, respectively.

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Prothymosin α and Its C-Terminal Immunoreactive Decapeptide Show no Evidence of Acute Toxicity: A Preliminary in Silico, in Vitro and in Vivo Investigation

Current Medicinal Chemistry ◽

10.2174/0929867328666211117093401 ◽

2021 ◽

Vol 28 ◽

Author(s):

Anastasios I. Birmpilis ◽

Panagiotis Vitsos ◽

Ioannis V. Kostopoulos ◽

Lillian Williams ◽

Kyriaki Ioannou ◽

...

Keyword(s):

Acute Toxicity ◽

In Silico ◽

Human Cancer ◽

Cell Cycle Distribution ◽

Human Cancer Cell Lines ◽

Prothymosin Α ◽

High Concentrations ◽

Immunocompetent Mice

Background: Members of the α-thymosin family have long been studied for their immunostimulating properties. Among them, the danger-associated molecular patterns (DAMPs) prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) have been shown to act as immunomodulators in vitro, due to their ability to promote T helper type 1 (Th1) responses. Recently, we verified these findings in vivo, showing that both proTα and proTα(100-109) enhance antitumor-reactive T cell-mediated responses. Methods: In view of the eventual use of proTα and proTα(100-109) in humans, we investigated their safety profile in silico, in human leukocytes and cancer cells lines in vitro, and in immunocompetent mice in vivo, in comparison to the proTα derivative thymosin alpha 1 (Τα1), a 28-mer peptide extensively studied for its safety in clinical trials. Results: In silico prediction via computational tools showed that all three peptide sequences likely are non-toxic or do not induce allergic regions. In vitro, proTα, proTα(100-109) and Tα1 did not affect the viability of human cancer cell lines and healthy donor-derived leukocytes, did not promote apoptosis or alter cell cycle distribution. Furthermore, mice injected with proTα, proTα(100-109) and Tα1 at doses equivalent to the suggested dose regimen of Tα1 in humans, did not show signs of acute toxicity, whereas proTα and proTα(100-109) increased the levels of proinflammatory and Th1-type cytokines in their peripheral blood. Conclusion: Our preliminary findings suggest that proTα and proTα(100-109), even at high concentrations, are non-toxic in vitro and in an acute toxicity model in vivo; moreover, we show that the two peptides retain their immunomodulatory properties in vivo and, eventually, could be considered for therapeutic use in humans.

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Eleucine indicaPossesses Antioxidant, Antibacterial and Cytotoxic Properties

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nep091 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 10

Author(s):

Adel S. Al-Zubairi ◽

Ahmad Bustamam Abdul ◽

Siddig Ibrahim Abdelwahab ◽

Chew Yuan Peng ◽

Syam Mohan ◽

...

Keyword(s):

Antibacterial Activity ◽

Human Cancer ◽

Antioxidant Properties ◽

Antibacterial Properties ◽

Diffusion Method ◽

Total Phenolic ◽

Significant Activity ◽

Human Cancer Cell Lines

The use of evidence-based complementary and alternative medicine is increasing rapidly.Eleucine indica(EI) is traditionally used in ailments associated with liver and kidneys. The therapeutic benefit of the medicinal plants is often attributed to their antioxidant properties. Therefore, the aim of this study was to screen the hexane, dicholoromethane, ethyl acetate (EA) and methanol extracts (MeTH) of EI for their antioxidant, antibacterial and anti-cancer effects using total phenolic contents (TPCs) and DPPH, disc diffusion method and MTT cytotoxicity assays, respectively. The MeTH was showed to have the highest TPC and scavenging activity (77.7%) on DPPH assay, followed by EA (64.5%), hexane (47.19%) and DCM (40.83%) extracts, whereas the MeTH showed no inhibitory effect on all tested bacteria strains. However, the EA extract exhibited a broad spectrum antibacterial activity against all tested bacteria exceptBacillus subtilis, in which this bacterium was found to be resistant to all EI extracts. Meanwhile, hexane extract was demonstrated to have a remarkable antibacterial activity against methicillin resistantStaphylococcus aureus(MRSA) andPseudomonas aeruginosa, while the dicholoromethane extract did not exhibit significant activity againstP. aeruginosa. None of the extracts showed significant cytotoxic activity towards MCF-7, HT-29 and CEM-SS human cancer cell lines after 72 h incubation time (IC50> 30 μg/ml). These results demonstrate that the extract prepared from the EI possesses antioxidant activityin vitroin addition to antibacterial properties. Further investigations are needed to verify the antioxidant effectsin vitroandin vivo.

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Cannabinoid Quinones—A Review and Novel Observations

Molecules ◽

10.3390/molecules26061761 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1761

Author(s):

Natalya M. Kogan ◽

Maximilian Peters ◽

Raphael Mechoulam

Keyword(s):

Human Cancer ◽

Mechanisms Of Action ◽

High Efficacy ◽

Topoisomerase Iiα ◽

Human Cancer Cell Lines ◽

Structure Activity ◽

Related Compounds ◽

Very High

A cannabinoid anticancer para-quinone, HU-331, which was synthesized by our group five decades ago, was shown to have very high efficacy against human cancer cell lines in-vitro and against in-vivo grafts of human tumors in nude mice. The main mechanism was topoisomerase IIα catalytic inhibition. Later, several groups synthesized related compounds. In the present presentation, we review the publications on compounds synthesized on the basis of HU-331, summarize their published activities and mechanisms of action and report the synthesis and action of novel quinones, thus expanding the structure-activity relationship in these series.

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Combination of Antiretroviral Drugs Zidovudine and Efavirenz Impairs Tumor Growths in a Mouse Model of Cancer

Viruses ◽

10.3390/v13122396 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2396

Author(s):

Marcel A. Schneider ◽

Anton A. Buzdin ◽

Achim Weber ◽

Pierre-Alain Clavien ◽

Pieter Borger

Keyword(s):

Target Gene ◽

Human Cancer ◽

Chromosomal Rearrangements ◽

Antiretroviral Drugs ◽

Colorectal Tumors ◽

Oncogenic Potential ◽

Reading Frame ◽

Human Cancer Cell Lines

LINE1 retrotransposons, which are thought to be the remnants of ancient integrations of retrovirus-like elements, are aberrantly (re)activated in many cancer cells. Due to LINE1-induced alterations in target gene expression and/or chromosomal rearrangements, they may be important drivers of tumorigenesis. Moreover, LINE1 encoded proteins, Open Reading Frame (ORF)1 and ORF2, may have pro-oncogenic potential through inductors of oncogenic transcription factors or inhibitors of cell cycle suppressors. The current study therefore aimed to investigate in vitro and in vivo anti-tumorigenic effects of two well-known antiretroviral drugs, zidovudine, a nucleoside analogue inhibitor of RT (NRTI), and efavirenz, a non-nucleoside RT inhibitor (NNRTI). Our data demonstrate that both drugs in clinically relevant doses significantly reduced the proliferation of murine and human cancer cell lines, as well as growth of tumors in a murine subcutaneous model. Intriguingly, we found that the combination of both zidovudine and efavirenz almost entirely blocked tumorigenesis in vivo. Because both drugs are FDA-approved agents and the combination was very well tolerated in mice, the combination therapy as presented in our paper might be an opportunity to treat colorectal tumors and metastasis to the liver in an inexpensive way.

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