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38 pages, 6040 KiB

Open AccessArticle

Anti-Cancer Mechanisms of Diarylpentanoid MS17 (1,5-Bis(2-hydroxyphenyl)-1,4-pentadiene-3-one) in Human Colon Cancer Cells: A Proteomics Approach

by Kha Wai Hon, Syafiq Asnawi Zainal Abidin, Faridah Abas, Iekhsan Othman and Rakesh Naidu

Int. J. Mol. Sci. 2024, 25(6), 3503; https://doi.org/10.3390/ijms25063503 - 20 Mar 2024

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Abstract

Diarylpentanoids are synthesized to overcome curcumin’s poor bioavailability and low stability to show enhanced anti-cancer effects. Little is known about the anti-cancer effects of diarylpentanoid MS17 (1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one) in colon cancer cells. This study aimed to elucidate molecular mechanisms and pathways modulated by MS17 [...] Read more.

Diarylpentanoids are synthesized to overcome curcumin’s poor bioavailability and low stability to show enhanced anti-cancer effects. Little is known about the anti-cancer effects of diarylpentanoid MS17 (1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one) in colon cancer cells. This study aimed to elucidate molecular mechanisms and pathways modulated by MS17 in colon cancer based on proteomic profiling of primary SW480 and metastatic SW620 colon cancer cells. Cytotoxicity and apoptotic effects of MS17 were investigated using MTT assay, morphological studies, and Simple Western analysis. Proteomic profiling using LC/MS analysis identified differentially expressed proteins (DEPs) in MS17-treated cells, with further analysis in protein classification, gene ontology enrichment, protein–protein interaction network and Reactome pathway analysis. MS17 had lower EC₅₀ values (SW480: 4.10 µM; SW620: 2.50 µM) than curcumin (SW480: 17.50 µM; SW620: 13.10 µM) with a greater anti-proliferative effect. MS17 treatment of 1× EC₅₀ induced apoptotic changes in the morphology of SW480 and SW620 cells upon 24 h treatment. A total of 24 and 92 DEPs (fold change ≥ 1.50) were identified in SW480 and SW620 cells, respectively, upon MS17 treatment of 2× EC₅₀ for 24 h. Pathway analysis showed that MS17 may induce its anti-cancer effects in both cells via selected DEPs associated with the top enriched molecular pathways. RPL and RPS ribosomal proteins, heat shock proteins (HSPs) and ubiquitin–protein ligases (UBB and UBC) were significantly associated with cellular responses to stress in SW480 and SW620 cells. Our findings suggest that MS17 may facilitate the anti-proliferative and apoptotic activities in primary (SW480) and metastatic (SW620) human colon cancer cells via the cellular responses to stress pathway. Further investigation is essential to determine the alternative apoptotic mechanisms of MS17 that are independent of caspase-3 activity and Bcl-2 protein expression in these cells. MS17 could be a potential anti-cancer agent in primary and metastatic colon cancer cells. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-cancer Therapies 2.0)

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33 pages, 4155 KiB

Open AccessArticle

Platinum(IV) Prodrugs Incorporating an Indole-Based Derivative, 5-Benzyloxyindole-3-Acetic Acid in the Axial Position Exhibit Prominent Anticancer Activity

by Angelico D. Aputen, Maria George Elias, Jayne Gilbert, Jennette A. Sakoff, Christopher P. Gordon, Kieran F. Scott and Janice R. Aldrich-Wright

Int. J. Mol. Sci. 2024, 25(4), 2181; https://doi.org/10.3390/ijms25042181 - 11 Feb 2024

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Abstract

Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand [...] Read more.

Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand that integrates an indole pharmacophore. The purity and chemical structures of the resultant complexes, P-5B3A, 5-5B3A and 56-5B3A were confirmed via spectroscopic means. The complexes were evaluated for anticancer activity against multiple human cell lines. All complexes proved to be considerably more active than cisplatin, oxaliplatin and carboplatin in most cell lines tested. Remarkably, 56-5B3A demonstrated the greatest anticancer activity, displaying GI₅₀ values between 1.2 and 150 nM. Enhanced production of reactive oxygen species paired with the decline in mitochondrial activity as well as inhibition of histone deacetylase were also demonstrated by the complexes in HT29 colon cells. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-cancer Therapies 2.0)

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15 pages, 2744 KiB

Open AccessArticle

Guanylation Reactions for the Rational Design of Cancer Therapeutic Agents

by Almudena del Campo-Balguerías, Blanca Parra-Cadenas, Cristina Nieto-Jimenez, Iván Bravo, Consuelo Ripoll, Elisa Poyatos-Racionero, Pawel Gancarski, Fernando Carrillo-Hermosilla, Carlos Alonso-Moreno and Alberto Ocaña

Int. J. Mol. Sci. 2023, 24(18), 13820; https://doi.org/10.3390/ijms241813820 - 07 Sep 2023

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Abstract

The modular synthesis of the guanidine core by guanylation reactions using commercially available ZnEt₂ as a catalyst has been exploited as a tool for the rapid development of antitumoral guanidine candidates. Therefore, a series of phenyl-guanidines were straightforwardly obtained in very high [...] Read more.

The modular synthesis of the guanidine core by guanylation reactions using commercially available ZnEt₂ as a catalyst has been exploited as a tool for the rapid development of antitumoral guanidine candidates. Therefore, a series of phenyl-guanidines were straightforwardly obtained in very high yields. From the in vitro assessment of the antitumoral activity of such structurally diverse guanidines, the guanidine termed ACB3 has been identified as the lead compound of the series. Several biological assays, an estimation of AMDE values, and an uptake study using Fluorescence Lifetime Imaging Microscopy were conducted to gain insight into the mechanism of action. Cell death apoptosis, induction of cell cycle arrest, and reduction in cell adhesion and colony formation have been demonstrated for the lead compound in the series. In this work, and as a proof of concept, we discuss the potential of the catalytic guanylation reactions for high-throughput testing and the rational design of guanidine-based cancer therapeutic agents. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-cancer Therapies 2.0)

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12 pages, 3535 KiB

Open AccessArticle

CBD Inhibits In Vivo Development of Human Breast Cancer Tumors

by Lázaro García-Morales, Mónica G. Mendoza-Rodríguez, José Tapia Ramírez and Isaura Meza

Int. J. Mol. Sci. 2023, 24(17), 13235; https://doi.org/10.3390/ijms241713235 - 26 Aug 2023

Cited by 1 | Viewed by 3688

Abstract

Inflammation is a critical component of cancer development. Previously, we showed in vitro that IL-1β treatment of non-invasive human breast cancer MCF-7 cells promoted their transition to a malignant phenotype (6D cells). This epithelial–mesenchymal transition was reverted by exposure to cannabidiol (CBD). We [...] Read more.

Inflammation is a critical component of cancer development. Previously, we showed in vitro that IL-1β treatment of non-invasive human breast cancer MCF-7 cells promoted their transition to a malignant phenotype (6D cells). This epithelial–mesenchymal transition was reverted by exposure to cannabidiol (CBD). We show in a murine model that subcutaneous inoculation of 6D cells induced formation and development of tumors, the cells of which keep traits of malignancy. These processes were interrupted by administration of CBD under two schemes: therapeutic and prophylactic. In the therapeutic scheme, 6D cells inoculated mice developed tumors that reached a mean volume of 540 mm³ at 45 days, while 50% of CBD-treated mice showed gradual resorption of tumors. In the prophylactic scheme, mice were pre-treated for 15 days with CBD before cells inoculation. The tumors formed remained small and were eliminated under continuous CBD treatment in 66% of the animals. Histological and molecular characterization of tumors, from both schemes, revealed that CBD-treated cells decreased the expression of malignancy markers and show traits related with apoptosis. These results confirm that in vivo CBD blocks development of breast cancer tumors formed by cells induced to malignancy by IL-1β, endorsing its therapeutic potential for cancer treatment. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-cancer Therapies 2.0)

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29 pages, 9027 KiB

Open AccessArticle

Docking Studies, Cytotoxicity Evaluation and Interactions of Binuclear Copper(II) Complexes with S-Isoalkyl Derivatives of Thiosalicylic Acid with Some Relevant Biomolecules

by Jelena D. Dimitrijević, Natalija Solovjova, Andriana M. Bukonjić, Dušan Lj. Tomović, Mirjana Milinkovic, Angelina Caković, Jovana Bogojeski, Zoran R. Ratković, Goran V. Janjić, Aleksandra A. Rakić, Nebojsa N. Arsenijevic, Marija Z. Milovanovic, Jelena Z. Milovanovic, Gordana P. Radić and Verica V. Jevtić

Int. J. Mol. Sci. 2023, 24(15), 12504; https://doi.org/10.3390/ijms241512504 - 06 Aug 2023

Cited by 1 | Viewed by 1450

Abstract

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5′-monophosphate and calf [...] Read more.

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5′-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1β, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-cancer Therapies 2.0)

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22 pages, 3147 KiB

Open AccessArticle

A FRET-Based Assay for the Identification of PCNA Inhibitors

by Sarah Hardebeck, Sebastian Schreiber, Annika Adick, Klaus Langer and Joachim Jose

Int. J. Mol. Sci. 2023, 24(14), 11858; https://doi.org/10.3390/ijms241411858 - 24 Jul 2023

Cited by 2 | Viewed by 1667

Abstract

Proliferating cell nuclear antigen (PCNA) is the key regulator of human DNA metabolism. One important interaction partner is p15, involved in DNA replication and repair. Targeting the PCNA–p15 interaction is a promising therapeutic strategy against cancer. Here, a Förster resonance energy transfer (FRET)-based [...] Read more.

Proliferating cell nuclear antigen (PCNA) is the key regulator of human DNA metabolism. One important interaction partner is p15, involved in DNA replication and repair. Targeting the PCNA–p15 interaction is a promising therapeutic strategy against cancer. Here, a Förster resonance energy transfer (FRET)-based assay for the analysis of the PCNA–p15 interaction was developed. Next to the application as screening tool for the identification and characterization of PCNA–p15 interaction inhibitors, the assay is also suitable for the investigation of mutation-induced changes in their affinity. This is particularly useful for analyzing disease associated PCNA or p15 variants at the molecular level. Recently, the PCNA variant C148S has been associated with Ataxia-telangiectasia-like disorder type 2 (ATLD2). ATLD2 is a neurodegenerative disease based on defects in DNA repair due to an impaired PCNA. Incubation time dependent FRET measurements indicated no effect on PCNA^C148S–p15 affinity, but on PCNA stability. The impaired stability and increased aggregation behavior of PCNA^C148S was confirmed by intrinsic tryptophan fluorescence, differential scanning fluorimetry (DSF) and asymmetrical flow field-flow fractionation (AF4) measurements. The analysis of the disease associated PCNA variant demonstrated the versatility of the interaction assay as developed. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-cancer Therapies 2.0)

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Review

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24 pages, 5367 KiB

Open AccessReview

Novel Matrix Metalloproteinase-9 (MMP-9) Inhibitors in Cancer Treatment

by Zainab Ahmed Rashid and Sanaa K. Bardaweel

Int. J. Mol. Sci. 2023, 24(15), 12133; https://doi.org/10.3390/ijms241512133 - 28 Jul 2023

Cited by 6 | Viewed by 2741

Abstract

Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of the most intricate MMPs. The crucial involvement of MMP-9 in extracellular matrix (ECM) remodeling underscores its significant correlation with [...] Read more.

Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of the most intricate MMPs. The crucial involvement of MMP-9 in extracellular matrix (ECM) remodeling underscores its significant correlation with each stage of cancer pathogenesis and progression. The design and synthesis of MMP-9 inhibitors is a potentially attractive research area. Unfortunately, to date, there is no effective MMP-9 inhibitor that passes the clinical trials and is approved by the FDA. This review primarily focuses on exploring the diverse strategies employed in the design and advancement of MMP-9 inhibitors, along with their anticancer effects and selectivity. To illuminate the essential structural characteristics necessary for the future design of novel MMP-9 inhibitors, the current narrative review highlights several recently discovered MMP-9 inhibitors exhibiting notable selectivity and potency. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-cancer Therapies 2.0)

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36 pages, 1848 KiB

Open AccessReview

Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment

by Yu-De Chu, Ming-Wei Lai and Chau-Ting Yeh

Int. J. Mol. Sci. 2023, 24(13), 10668; https://doi.org/10.3390/ijms241310668 - 26 Jun 2023

Cited by 1 | Viewed by 3324

Abstract

Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis—all of which are critical for tumor growth. These discoveries, coupled [...] Read more.

Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis—all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-cancer Therapies 2.0)

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