scholarly journals Near-Infrared MAO A Inhibitor (NMI) Outperformed FDA-Approved Chemotherapeutic Agents in Brain and Other Cancers: A Bioinformatic Analysis of NCI60 Screening Data

2021 ◽  
Vol 11 (10) ◽  
pp. 1318
Author(s):  
Qianhua Feng ◽  
Yuxuan Lian ◽  
Yihan Qian ◽  
Jean C. Shih
Keyword(s):  
Prostate Cancer ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Near Infrared ◽  
Chemotherapeutic Agents ◽  
Monoamine Oxidase A ◽  
Mao A ◽  
Cns Cancer ◽  
Cancer Prostate

Our previous work has shown that monoamine oxidase A (MAO A) is overexpressed in glioma and prostate cancer. Near-infrared dye conjugate MAO A Inhibitor (NMI) inhibited the growth of these cancers. This study investigated the effects of NMI on other cancers by NCI60 screening. Our results showed that 48 out of 59 screened cell lines from nine types of cancer had 100% growth inhibition at 10 μM NMI treatment. The in vitro efficacy of NMI determined by growth inhibition (GI50 and TGI) and lethal doses (LC50) has been further studied in various cell lines of CNS cancer, prostate cancer, and non-small cell lung cancer (NSCLC), these three cancers showed increased MAO A expression in tumors compared to normal tissues. Based on the waterfall plots and the 3D scatter plot of GI50, TGI, and LC50 data, NMI showed higher potency to several CNS cancer and NSCLC cell lines than prostate cancer cell lines. In vitro efficacy of NMI outperformed FDA-approved drugs for CNS cancer, prostate cancer, and NSCLC, respectively. The Pairwise Pearson Correlation Coefficient (PCC) showed that NMI has a unique mechanism compared to the existing anticancer drugs. This study shows that NMI is a novel theragnostic drug with high potency and unique mechanisms for brain, prostate, NSCLC, and other cancers.

scholarly journals The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2257 ◽  
Author(s):  
Najla O. Zarmouh ◽  
Samia S. Messeha ◽  
Nelly Mateeva ◽  
Madhavi Gangapuram ◽  
Kacy Flowers ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Docking ◽  
Monoamine Oxidase ◽  
Cell Lines ◽  
Monoamine Oxidase A ◽  
Hydroxyl Groups ◽  
Antiproliferative Effects ◽  
Mao B ◽  
Chlorine Substitution ◽  
Mao A

Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by establishing novel anti-PCa reversible monoamine oxidase-A inhibitors (MAO-AIs/RIMA); with an endeavor to understand their mechanism of action. In this investigation, twenty synthesized flavonoid derivatives, defined as KKR compounds were screened for their inhibitory potentials against human MAO-A and MAO-B isozymes. Meanwhile, the cytotoxic and antiproliferative effects were determined in three human PCa cell lines. MAO-A-kinetics, molecular docking, SAR, cell morphology, and cell migration were investigated for the most potent compounds. The screened KKRs inhibited MAO-A more potently than MAO-B, and non-toxically inhibited LNCaP cell proliferation more than the DU145 and PC3 cell lines, respectively. The results showed that the three top MAO-AI KKRs compounds (KKR11, KKR20, and KKR7 (IC50s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC50s ~9.4 μM). While KKR21 (MAO-AI) and KKR2A (MAO-I) were ineffective against the PCa cells. Furthermore, KKR21 and KKR11 inhibited MAO-A competitively (Kis ≤ 7.4 nM). Molecular docking of the two compounds predicted shared hydrophobic and distinctive hydrophilic interactions—between the KKR molecule and MAO-A amino acid residues—to be responsible for their reversibility. The combined results and SAR observations indicated that the presence of specific active groups—such as chlorine and hydroxyl groups—are essential in certain MAO-AIs with anti-PCa effects. Additionally, MAO-A inhibition was found to be associated more with anti-PCa property than MAO-B. Distinctively, KKR11 [(E)-3-(3,4-dichlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one] exhibited anti-metastatic effects on the DU145 cell line. The chlorine substitution groups might play vital roles in the KKR11 multiple actions. The obtained results indicated that the flavonoid derivative KKR11 could present a novel candidate for PCa patients with depression, through safe non-selective potent inhibition of MAOs.

Significance of targeting the antiapoptotic pathway in castration-sensitive prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 250-250
Author(s):  
Goutam Chakraborty ◽  
Rahim Hirani ◽  
Subhiksha Nandakumar ◽  
Teja Muralidhar Kalidindi ◽  
Deborah Fidele ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Lncap Cells ◽  
Mice Model ◽  
Over Expression ◽  
Hormone Sensitive ◽  
Bcl2 Expression

250 Background: Prostate cancer (PC) is a major health problem for men in the U.S. and is the second most common cause of cancer-related deaths in males. Although most PCs are initially sensitive to androgen-deprivation therapy (ADT), the duration of response is variable, and eventually, the cancer becomes resistant to ADT and progresses to metastatic castration-resistant prostate cancer (mCRPC). For mCRPC patients, many initially respond to second-line ARIs (eg. enzalutamide and abiraterone) or docetaxel-based chemotherapy however durable responses are rare. Therefore, it is vital to investigate additional therapeutic strategies to delay or prevent the transition of castration-sensitive prostate cancer (CSPC) to mCRPC. Methods: We treated castration-sensitive human PC cells with various anti-androgen inhibitors to investigate the direct association between Bcl2 expression and AR-pathway. We used a lentiviral-based over-expression method to develop BCL2 over-expressed experimental PC cell line systems and subjected them to various in -vitro and in vivo studies. We studied the combinational effect of Bcl2 and AR inhibitor on the in vitro growth of hormone-sensitive human PC cells and in vivo mice model. Results: We observed that treatment with androgen inhibits but ARIs (eg enzalutamide, apalutamide) restore Bcl2 expression in human CSPC cell lines indicating there is possible direct negative-regulation of the Bcl2 by the AR-signaling pathway. BCL2 over-expressed LNCaP cells show deregulation of the AR pathway, induces PSMA expression, and exhibit relative resistance to enzalutamide indicating that over-expression of BCL2 induces castration resistance in hormone-sensitive PC cells. Our cell growth inhibition assay showed an overall strong additive effect on growth inhibition with enzalutamide and the pharmacological Bcl2 inhibitor (venetoclax) combination on LNCaP cells and 22Rv1 cells. We also observed a negative association between BCL2 and AR pathway in clinical PC cohorts (Localized and mCRPC). In the isograft mice model, we showed the combination of enzalutamide and venetoclax significantly reduces subcutaneous prostate tumor growth and increases overall survival (~2 weeks) compare to control groups of mice. Moreover, using Isogenic cell lines (control and BCL2 over-expressed LNCaP) we showed higher uptake of [68Ga]-PSMA-11 in BCL2 over-expressed prostate tumors compared to control tumors in immunodeficient mice indicating that BCL2 over-expressed PC can monitor non-invasively by PSMA-PET imaging. Conclusions: Our current study develops a rationale for combining ADT with Bcl2-inhibitors for CSPC. We believe this combinatorial therapeutic approach will show great potential for future clinical trials of high-risk hormone-sensitive PC patients and may block the ADT-induced shift of CSPC to mCRPC.

New Mechanistic Insight on the PIM-1 Kinase Inhibitor AZD1208 Using Multidrug Resistant Human Erythroleukemia Cell Lines and Molecular Docking Simulations

2019 ◽  
Vol 19 (11) ◽  
pp. 914-926 ◽  
Author(s):  
Maiara Bernardes Marques ◽  
Michael González-Durruthy ◽  
Bruna Félix da Silva Nornberg ◽  
Bruno Rodrigues Oliveira ◽  
Daniela Volcan Almeida ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Site ◽  
Cell Lines ◽  
Chemotherapeutic Agents ◽  
Atp Binding ◽  
Human Leukemia ◽  
Atp Binding Site ◽  
Mechanistic Insight ◽  
Multiple Drugs

Background:PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation, and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype.Objective:In the present work, we tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR).Materials and Methods:In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line, by MTT analyses. The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123. Furthermore, we performed a molecular docking simulation to delve into the molecular mechanism of PIM-1 alone, and combined with chemotherapeutic agents (VCR and DNR).Results:Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Docking analysis showed that AZD1208 is capable of performing hydrophobic interactions with PIM-1 ATP- binding-site residues with stronger interaction-based negative free energy (FEB, kcal/mol) than the ATP itself, mimicking an ATP-competitive inhibitory pattern of interaction. On the same way, VCR and DNR may theoretically interact at the same biophysical environment of AZD1208 and also compete with ATP by the PIM-1 active site. These evidences suggest that AZD1208 may induce pharmacodynamic interaction with VCR and DNR, weakening its cytotoxic potential in the ATP-binding site from PIM-1 observed in the in vitro experiments.Conclusion:Finally, the current results could have a pre-clinical relevance potential in the rational polypharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy.

scholarly journals Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioiso-Mers for Antimalarial, Antiproliferative and Antimicrobial Activities

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3268
Author(s):  
Katja S. Håheim ◽  
Emil Lindbäck ◽  
Kah Ni Tan ◽  
Marte Albrigtsen ◽  
Ida T. Urdal Helgeland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antimicrobial Activities ◽  
Ring System ◽  
Human Prostate ◽  
The Novel ◽  
Human Prostate Cancer ◽  
Biofilm Inhibition

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).

scholarly journals Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Denisa Baci ◽  
Antonino Bruno ◽  
Caterina Cascini ◽  
Matteo Gallazzi ◽  
Lorenzo Mortara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Dietary Supplements ◽  
Cell Lines ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Prostate Cancer Cells

Abstract Background Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

scholarly journals Implementation of the NCI-60 Human Tumor Cell Line Panel to Screen 2260 Cancer Drug Combinations to Generate >3 Million Data Points Used to Populate a Large Matrix of Anti-Neoplastic Agent Combinations (ALMANAC) Database

2018 ◽  
Vol 24 (3) ◽  
pp. 242-263 ◽  
Author(s):  
David A. Close ◽  
Allen Xinwei Wang ◽  
Stanton J. Kochanek ◽  
Tongying Shun ◽  
Julie L. Eiseman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Growth Inhibition ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Cancer Drug ◽  
Large Matrix ◽  
Data Points

Animal and clinical studies demonstrate that cancer drug combinations (DCs) are more effective than single agents. However, it is difficult to predict which DCs will be more efficacious than individual drugs. Systematic DC high-throughput screening (HTS) of 100 approved drugs in the National Cancer Institute’s panel of 60 cancer cell lines (NCI-60) produced data to help select DCs for further consideration. We miniaturized growth inhibition assays into 384-well format, increased the fetal bovine serum amount to 10%, lengthened compound exposure to 72 h, and used a homogeneous detection reagent. We determined the growth inhibition 50% values of individual drugs across 60 cell lines, selected drug concentrations for 4 × 4 DC matrices (DCMs), created DCM master and replica daughter plate sets, implemented the HTS, quality control reviewed the data, and analyzed the results. A total of 2620 DCMs were screened in 60 cancer cell lines to generate 3.04 million data points for the NCI ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations) database. We confirmed in vitro a synergistic drug interaction flagged in the DC HTS between the vinca-alkaloid microtubule assembly inhibitor vinorelbine (Navelbine) tartrate and the epidermal growth factor-receptor tyrosine kinase inhibitor gefitinib (Iressa) in the SK-MEL-5 melanoma cell line. Seventy-five percent of the DCs examined in the screen are not currently in the clinical trials database. Selected synergistic drug interactions flagged in the DC HTS described herein were subsequently confirmed by the NCI in vitro, evaluated mechanistically, and were shown to have greater than single-agent efficacy in mouse xenograft human cancer models. Enrollment is open for two clinical trials for DCs that were identified in the DC HTS. The NCI ALMANAC database therefore constitutes a valuable resource for selecting promising DCs for confirmation, mechanistic studies, and clinical translation.

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