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Cancer Targeted Small Molecules

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 (15 May 2023) | Viewed by 21484

Special Issue Editor

Department of Bio-resources and Food Science, Konkuk University, Seoul 143-701, Korea
Interests: cancer cell biology; immunofluorescence; bioinformatics; virology; immunoblotting

Special Issue Information

Dear Colleagues

Cancer is a global health problem that affects all communities around the world due to its significant social impact and high economic cost. Small-molecule-based chemotherapy is sadly unable to differentiate between normal cells and cancer cells, resulting in significant side effects. However, targeted drug developments are breaking the limitations of small molecule usage in anticancer drug development. Targeted drugs can be broadly classified into two categories, small molecules and macromolecules. Targeted small molecule drugs are more applicable in some aspects than macromolecules, including pharmacokinetic properties, cost, patient compliance, drug storage, and transportation. Compared with traditional chemotherapy drugs, targeted drugs can specifically target cancer cells, so they have high efficacy and low toxicity. The targeted drugs cover a wide range of fields, including kinases, epigenetic regulatory proteins, DNA damage repair enzymes, and proteasomes. Moreover, recently anticancer immune modulatory targeted small molecules are under development by a number of research teams and biotech companies. Additionally, development of computational biology promotes it accurate, faster, and cheaper targeted drug development with artificial intelligence and machine learning techniques.

Therefore, this Special Issue is dedicated to original research articles, short communications, and reviews which cover the latest findings on targeted anticancer small molecules (including phytochemicals), and especially their biological activity, efficacy, and mechanism of action in vitro, in vivo, and in silico. In this  Issue, research on small molecules with unknown compositions is not welcomed.

Dr. Gansukh Enkhtaivan
Guest Editor

Manuscript Submission Information

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Keywords

  • Anticancer
  • Small molecules
  • Targeted therapy
  • Cytotoxicity
  • Chemokine
  • Phytochemical

Published Papers (7 papers)

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Research

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17 pages, 41926 KiB  
Article
Berberine Induces Combined Cell Death in Gastrointestinal Cell Lines
by Shiori Mori, Rina Fujiwara-Tani, Momoko Gyoten, Shota Nukaga, Rika Sasaki, Ayaka Ikemoto, Ruiko Ogata, Shingo Kishi, Kiyomu Fujii and Hiroki Kuniyasu
Int. J. Mol. Sci. 2023, 24(7), 6588; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076588 - 01 Apr 2023
Cited by 5 | Viewed by 2129
Abstract
Berberine (BBR) is a plant alkaloid that has various biological activities. The effects of BBR on gastrointestinal cancer (GIC) have also been investigated and anti-tumor effects such as induction of cell death have been reported. However, the mechanism of BBR-induced cell death has [...] Read more.
Berberine (BBR) is a plant alkaloid that has various biological activities. The effects of BBR on gastrointestinal cancer (GIC) have also been investigated and anti-tumor effects such as induction of cell death have been reported. However, the mechanism of BBR-induced cell death has not been fully elucidated. To this end, we investigated the effects of BBR using three GIC cell lines. Our analyses revealed that BBR inhibited cell proliferation, invasion, sphere formation, and anticancer drug resistance in all of the cell lines. BBR also induced an increase in mitochondrial superoxide, lipid peroxide and Fe2+ levels, decreased mitochondrial membrane potential and respiration, decreased glutathione peroxidase 4 expression and glutathione and induced Parkin/PINK1-associated mitophagy. BBR, as well as rotenone, inhibited mitochondrial complex I and enhanced complex II, which were associated with autophagy, reactive oxidative species production, and cell death. Inhibition of complex II by malonate abrogated these changes. BBR-induced cell death was partially rescued by ferrostatin-1, deferoxamine, Z-VAD-FMK, and ATG5 knockdown. Furthermore, oral administration of BBR significantly reduced tumor weight and ascites in a syngeneic mouse peritoneal metastasis model using CT26 GIC cells. These findings suggest that BBR induced a combined type of cell death via complex I inhibition and autophagy. The marked anti-tumor and anti-stemness effects are expected to be useful as a new cell death-inducing agent for the treatment of GIC. Full article
(This article belongs to the Special Issue Cancer Targeted Small Molecules)
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13 pages, 2834 KiB  
Article
A Sulfur Containing Melanogenesis Substrate, N-Pr-4-S-CAP as a Potential Source for Selective Chemoimmunotherapy of Malignant Melanoma
by Yasuaki Tamura, Akira Ito, Kazumasa Wakamatsu, Toshihiko Torigoe, Hiroyuki Honda, Shosuke Ito and Kowichi Jimbow
Int. J. Mol. Sci. 2023, 24(6), 5235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065235 - 09 Mar 2023
Viewed by 1240
Abstract
N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) is a substrate for tyrosinase, which is a melanin biosynthesis enzyme and has been shown to be selectively incorporated into melanoma cells. It was found to cause selective cytotoxicity against melanocytes and melanoma cells [...] Read more.
N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) is a substrate for tyrosinase, which is a melanin biosynthesis enzyme and has been shown to be selectively incorporated into melanoma cells. It was found to cause selective cytotoxicity against melanocytes and melanoma cells after selective incorporation, resulting in the induction of anti-melanoma immunity. However, the underlying mechanisms for the induction of anti-melanoma immunity remain unclear. This study aimed to elucidate the cellular mechanism for the induction of anti-melanoma immunity and clarify whether N-Pr-4-S-CAP administration could be a new immunotherapeutic approach against melanoma, including local recurrence and distant metastasis. A T cell depletion assay was used for the identification of the effector cells responsible for N-Pr-4-S-CAP-mediated anti-melanoma immunity. A cross-presentation assay was carried out by using N-Pr-4-S-CAP-treated B16-OVA melanoma-loaded bone marrow-derived dendritic cells (BMDCs) and OVA-specific T cells. Administration of N-Pr-4-S-CAP induced CD8+ T cell-dependent anti-melanoma immunity and inhibited the growth of challenged B16F1 melanoma cells, indicating that the administration of N-Pr-4-S-CAP can be a prophylactic therapy against recurrence and metastasis of melanoma. Moreover, intratumoral injection of N-Pr-4-S-CAP in combination with BMDCs augmented the tumor growth inhibition when compared with administration of N-Pr-4-S-CAP alone. BMDCs cross-presented a melanoma-specific antigen to CD8+ T cells through N-Pr-4-S-CAP-mediated melanoma cell death. Combination therapy using N-Pr-4-S-CAP and BMDCs elicited a superior anti-melanoma effect. These results suggest that the administration of N-Pr-4-S-CAP could be a new strategy for the prevention of local recurrence and distant metastasis of melanoma. Full article
(This article belongs to the Special Issue Cancer Targeted Small Molecules)
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27 pages, 8818 KiB  
Article
Genistein and Procyanidin B2 Reduce Carcinogen-Induced Reactive Oxygen Species and DNA Damage through the Activation of Nrf2/ARE Cell Signaling in Bronchial Epithelial Cells In Vitro
by Tharindu L. Suraweera, J. P. Jose Merlin, Graham Dellaire, Zhaolin Xu and H. P. Vasantha Rupasinghe
Int. J. Mol. Sci. 2023, 24(4), 3676; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043676 - 12 Feb 2023
Cited by 7 | Viewed by 2009
Abstract
Cancer is one of the leading causes of death worldwide. Chemotherapy and radiation therapy are currently providing the basis for cancer therapies, although both are associated with significant side effects. Thus, cancer prevention through dietary modifications has been receiving growing interest. The potential [...] Read more.
Cancer is one of the leading causes of death worldwide. Chemotherapy and radiation therapy are currently providing the basis for cancer therapies, although both are associated with significant side effects. Thus, cancer prevention through dietary modifications has been receiving growing interest. The potential of selected flavonoids in reducing carcinogen-induced reactive oxygen species (ROS) and DNA damage through the activation of nuclear factor erythroid 2 p45 (NF-E2)-related factor (Nrf2)/antioxidant response element (ARE) pathway was studied in vitro. Dose-dependent effects of pre-incubated flavonoids on pro-carcinogen 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKAc)-induced ROS and DNA damage in human bronchial epithelial cells were studied in comparison to non-flavonoids. The most effective flavonoids were assessed for the activation of Nrf2/ARE pathway. Genistein, procyanidin B2 (PCB2), and quercetin significantly suppressed the NNKAc-induced ROS and DNA damage. Quercetin significantly upregulated the phosphorylated protein kinase B/Akt. PCB2 significantly upregulated the activation of Nrf2 and Akt through phosphorylation. Genistein and PCB2 significantly upregulated the phospho-Nrf2 nuclear translocation and catalase activity. In summary, genistein and PCB2 reduced the NNKAc-induced ROS and DNA damage through the activation of Nrf2. Further studies are required to understand the role of dietary flavonoids on the regulation of the Nrf2/ARE pathway in relation to carcinogenesis. Full article
(This article belongs to the Special Issue Cancer Targeted Small Molecules)
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11 pages, 3676 KiB  
Article
Identification of Novel Artemisinin Hybrids Induce Apoptosis and Ferroptosis in MCF-7 Cells
by Ye Zhong, Zhi-Ning Li, Xin-Yue Jiang, Xing Tian, Ming-Hui Deng, Mao-Sheng Cheng, Hua-Li Yang and Yang Liu
Int. J. Mol. Sci. 2022, 23(24), 15768; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415768 - 12 Dec 2022
Cited by 1 | Viewed by 1431
Abstract
A series of novel 1,3,4-oxadiazole-artemisinin hybrids have been designed and synthesized. An MTT assay revealed that most of tested hybrids showed more enhanced anti-proliferative activities than artemisinin, among which A8 had the superior potency with IC50 values ranging from 4.07 μM to [...] Read more.
A series of novel 1,3,4-oxadiazole-artemisinin hybrids have been designed and synthesized. An MTT assay revealed that most of tested hybrids showed more enhanced anti-proliferative activities than artemisinin, among which A8 had the superior potency with IC50 values ranging from 4.07 μM to 9.71 μM against five tested cancer cell lines. Cell colony formation assays showed that A8 could inhibit significantly more cell proliferation than artemisinin and 5-fluorouracil. Further mechanism studies reveal that A8 induces apoptosis and ferroptosis in MCF-7 cells in a dose-dependent manner, and CYPs inhibition assays reveal that A8 has a moderate inhibitory effect on CYP1A2 and CYP3A4 in the human body at 10 μM. The present work indicates that hybrid A8 may merit further investigation as a potential therapeutic agent. Full article
(This article belongs to the Special Issue Cancer Targeted Small Molecules)
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26 pages, 13046 KiB  
Article
Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach
by Mohamed R. Abdelaal, Esraa Ibrahim, Mohamed R. Elnagar, Sameh H. Soror and Hesham Haffez
Int. J. Mol. Sci. 2022, 23(16), 9442; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169442 - 21 Aug 2022
Cited by 3 | Viewed by 2062
Abstract
Colorectal cancer therapies have produced promising clinical responses, but tumor cells rapidly develop resistance to these drugs. It has been previously shown that EC19 and EC23, two EC-synthetic retinoids, have single-agent preclinical anticancer activity in colorectal carcinoma. Here, isobologram analysis revealed that they [...] Read more.
Colorectal cancer therapies have produced promising clinical responses, but tumor cells rapidly develop resistance to these drugs. It has been previously shown that EC19 and EC23, two EC-synthetic retinoids, have single-agent preclinical anticancer activity in colorectal carcinoma. Here, isobologram analysis revealed that they have synergistic cytotoxicity with retinoic acid receptor (RAR) isoform-selective agonistic retinoids such as AC261066 (RARβ2-selective agonist) and CD437 (RARγ-selective agonist) in Caco-2 cells. This synergism was confirmed by calculating the combination index (lower than 1) and the dose reduction index (higher than 1). Flow cytometry of combinatorial IC50 (the concentration causing 50% cell death) confirmed the cell cycle arrest at the SubG0-G1 phase with potentiated apoptotic and necrotic effects. The reported synergistic anticancer activity can be attributed to their ability to reduce the expression of ATP-binding cassette (ABC) transporters including P-glycoprotein (P-gp1), breast cancer resistance protein (BCRP) and multi-drug resistance-associated protein-1 (MRP1) and Heat Shock Protein 70 (Hsp70). This adds up to the apoptosis-promoting activity of EC19 and EC23, as shown by the increased Caspase-3/7 activities and DNA fragmentation leading to DNA double-strand breaks. This study sheds the light on the possible use of EC-synthetic retinoids in the rescue of multi-drug resistance in colorectal cancer using Caco-2 as a model and suggests new promising combinations between different synthetic retinoids. The current in vitro results pave the way for future studies on these compounds as possible cures for colorectal carcinoma. Full article
(This article belongs to the Special Issue Cancer Targeted Small Molecules)
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Review

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19 pages, 1138 KiB  
Review
Ursolic Acid against Prostate and Urogenital Cancers: A Review of In Vitro and In Vivo Studies
by Amanda Kornel, Matteo Nadile, Maria Ilektra Retsidou, Minas Sakellakis, Katerina Gioti, Apostolos Beloukas, Newman Siu Kwan Sze, Panagiota Klentrou and Evangelia Tsiani
Int. J. Mol. Sci. 2023, 24(8), 7414; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087414 - 18 Apr 2023
Cited by 4 | Viewed by 1802
Abstract
Prostate cancer is the second most diagnosed form of cancer in men worldwide and accounted for roughly 1.3 million cases and 359,000 deaths globally in 2018, despite all the available treatment strategies including surgery, radiotherapy, and chemotherapy. Finding novel approaches to prevent and [...] Read more.
Prostate cancer is the second most diagnosed form of cancer in men worldwide and accounted for roughly 1.3 million cases and 359,000 deaths globally in 2018, despite all the available treatment strategies including surgery, radiotherapy, and chemotherapy. Finding novel approaches to prevent and treat prostate and other urogenital cancers effectively is of major importance. Chemicals derived from plants, such as docetaxel and paclitaxel, have been used in cancer treatment, and in recent years, research interest has focused on finding other plant-derived chemicals that can be used in the fight against cancer. Ursolic acid, found in high concentrations in cranberries, is a pentacyclic triterpenoid compound demonstrated to have anti-inflammatory, antioxidant, and anticancer properties. In the present review, we summarize the research studies examining the effects of ursolic acid and its derivatives against prostate and other urogenital cancers. Collectively, the existing data indicate that ursolic acid inhibits human prostate, renal, bladder, and testicular cancer cell proliferation and induces apoptosis. A limited number of studies have shown significant reduction in tumor volume in animals xenografted with human prostate cancer cells and treated with ursolic acid. More animal studies and human clinical studies are required to examine the potential of ursolic acid to inhibit prostate and other urogenital cancers in vivo. Full article
(This article belongs to the Special Issue Cancer Targeted Small Molecules)
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19 pages, 1605 KiB  
Review
Health Benefits of Coffee Consumption for Cancer and Other Diseases and Mechanisms of Action
by Stephen Safe, Jainish Kothari, Amanuel Hailemariam, Srijana Upadhyay, Laurie A. Davidson and Robert S. Chapkin
Int. J. Mol. Sci. 2023, 24(3), 2706; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032706 - 31 Jan 2023
Cited by 7 | Viewed by 10138
Abstract
Coffee is one of the most widely consumed beverages worldwide, and epidemiology studies associate higher coffee consumption with decreased rates of mortality and decreased rates of neurological and metabolic diseases, including Parkinson’s disease and type 2 diabetes. In addition, there is also evidence [...] Read more.
Coffee is one of the most widely consumed beverages worldwide, and epidemiology studies associate higher coffee consumption with decreased rates of mortality and decreased rates of neurological and metabolic diseases, including Parkinson’s disease and type 2 diabetes. In addition, there is also evidence that higher coffee consumption is associated with lower rates of colon and rectal cancer, as well as breast, endometrial, and other cancers, although for some of these cancers, the results are conflicting. These studies reflect the chemopreventive effects of coffee; there is also evidence that coffee consumption may be therapeutic for some forms of breast and colon cancer, and this needs to be further investigated. The mechanisms associated with the chemopreventive or chemotherapeutic effects of over 1000 individual compounds in roasted coffee are complex and may vary with different diseases. Some of these mechanisms may be related to nuclear factor erythroid 2 (Nrf2)-regulated pathways that target oxidative stress or pathways that induce reactive oxygen species to kill diseased cells (primarily therapeutic). There is evidence for the involvement of receptors which include the aryl hydrocarbon receptor (AhR) and orphan nuclear receptor 4A1 (NR4A1), as well as contributions from epigenetic pathways and the gut microbiome. Further elucidation of the mechanisms will facilitate the potential future clinical applications of coffee extracts for treating cancer and other inflammatory diseases. Full article
(This article belongs to the Special Issue Cancer Targeted Small Molecules)
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