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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 10975

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Dr. Alexander Shtil

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Blokhin Cancer Center and Institute of Gene Biology, Russian Academy of Sciences, 24 Kashirskoye Shosse, 115478 Moscow, Russia
Interests: intracellular signaling; cancer; chemotherapy; molecular targets; drug design; computational chemistry
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Special Issue Information

Dear Colleagues,

Intracellular signaling, a language understandable by biological structures, is an astonishingly smart system of cues and responses. Throughout the entire life span this language remains the major source of communication between the organism and the surrounding milieu, between the cells within the tissue, and between the molecules in the cells. Moreover, disease as a sustained deregulation of signaling can be considered a misspelling and misunderstanding.

To expand our knowledge about signaling the researchers need instruments that selectively interact with individual cellular targets. Calling these instruments the exogenous cues we expect the specific cellular replies. Therapeutically speaking, our instruments represent the mechanism-based drug candidates.

I am pleased to propose a Special Issue entitled "Chemical Tools for Targeted Cancer Therapy". I foresee this volume as a compendium of novel trends in chemistry and biology of antitumor agents (mostly, but not exclusively, low molecular weight compounds). New and established targets will be evaluated from the perspective of engagement by chemical instruments. Therefore studies of in silico and experimental interactions of drug candidates with tentative or established targets are welcome. Most importantly, what are the results of these interactions at the subcellular and cellular levels and in the clinic? Finally, of the exceptional value is critical re-evaluation of targeted anticancer treatment via dissection of this concept’s pros and contras.

Dr. Alexander Shtil
Guest Editor

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Keywords

intracellular signaling
cancer
chemotherapy
molecular targets
drug design
computational chemistry

Published Papers (4 papers)

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Research

17 pages, 5383 KiB

Open AccessArticle

Synthesis and Anti-Cancer Activity of New Pyrazolinyl-Indole Derivatives: Pharmacophoric Interactions and Docking Studies for Identifying New EGFR Inhibitors

by Habibullah Khalilullah, Deepak K. Agarwal, Mohamed J. Ahsan, Surender S. Jadav, Hamdoon A. Mohammed, Masood Alam Khan, Salman A. A. Mohammed and Riaz Khan

Int. J. Mol. Sci. 2022, 23(12), 6548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126548 - 11 Jun 2022

Cited by 4 | Viewed by 1736

Abstract

Newly designed series of indole-containing pyrazole analogs, pyrazolinylindoles, were synthesized, and their structures were confirmed based on the spectral data of the ¹H NMR, ¹³C NMR, and HR-MS analyses. Preliminary anti-cancer activity testings were carried out by the National Cancer Institute, United States of America (NCI, USA). Compounds HD02, HD05, and HD12 demonstrated remarkable cytotoxic activities against nine categories of cancer types based cell line panels which included leukemia, colon, breast, melanoma, lungs, renal, prostate, CNS, and ovarian cancer cell lines. The highest cytotoxic effects were exhibited by the compounds HD02 [1-(5-(1-H-indol-3-yl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-phenylethanone], HD05 [1-(3-(4-chlorophenyl)-5-(1H-indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-phenoxyethanone], and HD12 [(3-(4-chlorophenyl)-5-(1H-indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone] against some of the 56 types of NCI-based cell lines in different panels. Compound HD05 showed the maximum range of cancer cell growth inhibitions against all categories of the cell lines in all nine panels. On average, in comparison to the referral standard, imatinib, at a dose level of 10 µM, the HD05 showed significant activity against leukemia in the range of 78.76%, as compared to the imatinib at 9% of cancer cells’ growth inhibitions. Molecular docking simulation studies were performed in silico on the epidermal growth factor receptor (EGFR) tyrosine kinase, in order to validate the activity. Full article

(This article belongs to the Special Issue Frontiers in Chemical Tools for Targeted Cancer Therapy)

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16 pages, 1837 KiB

Open AccessArticle

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

by Mahamat Babagana, Lorin R. Brown, Hannah Z. Slabodkin, Julia V. Kichina and Eugene S. Kandel

Int. J. Mol. Sci. 2021, 22(21), 11376; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111376 - 21 Oct 2021

Cited by 1 | Viewed by 1605

Abstract

Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be stressful to a cell. In an attempt to better elucidate this phenomenon, we observed the signs of proteotoxic stress in cells that harbor hyperactive AKT or have lost its principal negative regulator, PTEN. The activity of HSF1 was predictably elevated under these circumstances. However, such cells proved more sensitive to various regimens of heat shock, including the conditions that were well-tolerated by syngeneic cells without AKT hyperactivity. The sensitizing effect of hyperactive AKT was also seen in HSF1-deficient cells, suggesting that the phenomenon does not require the regulation of HSF1 by this kinase. Notably, the elevated activity of AKT was accompanied by increased levels of XBP1, a key component of cell defense against proteotoxic stress. Interestingly, the cells harboring hyperactive AKT were also more dependent on XBP1 for their growth. Our observations suggest that proteotoxic stress conferred by hyperactive AKT represents a targetable vulnerability, which can be exploited by either elevating the stress above the level tolerated by such cells or by eliminating the factors that enable such tolerance. Full article

(This article belongs to the Special Issue Frontiers in Chemical Tools for Targeted Cancer Therapy)

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19 pages, 2288 KiB

Open AccessArticle

Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst

by Sergey A. Tsymbal, Anna A. Moiseeva, Nikol A. Agadzhanian, Svetlana S. Efimova, Alina A. Markova, Dmitry A. Guk, Olga O. Krasnovskaya, Victoria M. Alpatova, Andrei V. Zaitsev, Anna V. Shibaeva, Victor V. Tatarskiy, Marina S. Dukhinova, Valentina A. Ol’shevskaya, Olga S. Ostroumova, Elena K. Beloglazkina and Alexander A. Shtil

Int. J. Mol. Sci. 2021, 22(20), 11065; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011065 - 14 Oct 2021

Cited by 9 | Viewed by 2949

Abstract

Copper-containing agents are promising antitumor pharmaceuticals due to the ability of the metal ion to react with biomolecules. In the current study, we demonstrate that inorganic Cu²⁺ in the form of oxide nanoparticles (NPs) or salts, as well as Cu ions in the context of organic complexes (oxidation states +1, +1.5 and +2), acquire significant cytotoxic potency (2–3 orders of magnitude determined by IC₅₀ values) in combinations with N-acetylcysteine (NAC), cysteine, or ascorbate. In contrast, other divalent cations (Zn, Fe, Mo, and Co) evoked no cytotoxicity with these combinations. CuO NPs (0.1–1 µg/mL) together with 1 mM NAC triggered the formation of reactive oxygen species (ROS) within 2–6 h concomitantly with perturbation of the plasma membrane and caspase-independent cell death. Furthermore, NAC potently sensitized HCT116 colon carcinoma cells to Cu–organic complexes in which the metal ion coordinated with 5-(2-pyridylmethylene)-2-methylthio-imidazol-4-one or was present in the coordination sphere of the porphyrin macrocycle. The sensitization effect was detectable in a panel of mammalian tumor cell lines including the sublines with the determinants of chemotherapeutic drug resistance. The components of the combination were non-toxic if added separately. Electrochemical studies revealed that Cu cations underwent a stepwise reduction in the presence of NAC or ascorbate. This mechanism explains differential efficacy of individual Cu–organic compounds in cell sensitization depending on the availability of Cu ions for reduction. In the presence of oxygen, Cu⁺¹ complexes can generate a superoxide anion in a Fenton-like reaction Cu⁺¹L + O₂ → O₂^−. + Cu⁺²L, where L is the organic ligand. Studies on artificial lipid membranes showed that NAC interacted with negatively charged phospholipids, an effect that can facilitate the penetration of CuO NPs across the membranes. Thus, electrochemical modification of Cu ions and subsequent ROS generation, as well as direct interaction with membranes, represent the mechanisms of irreversible membrane damage and cell death in response to metal reduction in inorganic and organic Cu-containing compounds. Full article

(This article belongs to the Special Issue Frontiers in Chemical Tools for Targeted Cancer Therapy)

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23 pages, 3811 KiB

Open AccessArticle

Diclofenac N-Derivatives as Therapeutic Agents with Anti-Inflammatory and Anti-Cancer Effect

by Alberto Galisteo, Fatin Jannus, Amalia García-García, Houssam Aheget, Sara Rojas, José A. Lupiañez, Antonio Rodríguez-Diéguez, Fernando J. Reyes-Zurita and José F. Quílez del Moral

Int. J. Mol. Sci. 2021, 22(10), 5067; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105067 - 11 May 2021

Cited by 23 | Viewed by 3685

Abstract

A series of diclofenac N-derivatives (2, 4, 6, 8c, 9c, 10a-c) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound 8c against all cell lines and both compounds 4 and 6 in human Hep-G2 and HT29 cell lines. Compounds 4 and 8c were selected for the percentage of apoptosis determination, cell cycle distribution, and mitochondrial membrane potential measure because these products presented the lowest IC₅₀ values in two of the three cancer cell lines assayed (B16-F10 and HepG2), and were two of the three products with lowest IC₅₀ in HT29 cell line. Moreover, the percentages of apoptosis induction were determined for compounds 4 and 8c, showing that the highest values were between 30 to 60%. Next, the effects of these two compounds were observed on the cellular cycle, resulting in an increase in the cell population in G2/M cell cycle phase after treatment with product 8c, whereas compound 4 increased the cells in phase G0/G1, by possible differentiation process induction. Finally, to determine the possible apoptosis mechanism triggered by these compounds, mitochondrial potential was evaluated, indicating the possible activation of extrinsic apoptotic mechanism. On the other hand, we studied the anti-inflammatory effects of these diclofenac (DCF) derivatives on lipopolysaccharide (LPS) activated RAW 264.7 macrophages-monocytes murine cells by inhibition of nitric oxide (NO) production. As a first step, we determined the cytotoxicity of the synthesized compounds, as well as DCF, against these cells. Then, sub-cytotoxic concentrations were used to determine NO release at different incubation times. The greatest anti-inflammatory effect was observed for products 2, 4, 8c, 10a, 10b, and 9c at 20 µg·mL⁻¹ concentration after 48 h of treatment, with inhibition of produced NO between 60 to 75%, and a concentration that reduces to the 50% the production of NO (IC_{50 NO}) between 2.5 to 25 times lower than that of DCF. In this work, we synthesized and determined for the first time the anti-cancer and anti-inflammatory potential of eight diclofenac N-derivatives. In agreement with the recent evidences suggesting that inflammation may contribute to all states of tumorigenesis, the development of these new derivatives capable of inducing apoptosis and anti-inflammatory effects at very low concentrations represent new effective therapeutic strategies against these diseases. Full article

(This article belongs to the Special Issue Frontiers in Chemical Tools for Targeted Cancer Therapy)

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