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Anti-Cancer Drug: Discovery, Development and Combination

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 33153

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Special Issue Editor

Dr. Yasuyoshi Miyata

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Guest Editor

Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Interests: anti-cancer drugs; promising anti-cancer targets; translational research; clinical trials conservative therapy; peri-operative therapy; quality of life; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is recognized as a multifactorial disease and its progression is regulated by extremely complex mechanisms. Indeed, numerous factors, such as DNA methylation, miRNA, growth factors, angiogenesis, and the immune system, are closely associated with carcinogenesis, invasion, metastasis, and prognosis. In addition, a variety of molecules, cancer stem cells, and long non-coding RNAs play important roles in the resistance to cancer therapies. Furthermore, the contribution of such carcinogenic factors to malignant behavior is dependent on the type of cancer and the stage of the disease.

Armed with this knowledge, researchers have discovered many promising candidates for cancer therapy, and some are now being tested in clinical trials. Various new therapeutic targets, including chemical compounds and natural products, have been identified from basic and translational studies.

The aim of this Special Issue is to collect research papers, reviews, and communications focused on the discovery and development of anti-cancer drugs, as well as potential therapeutic targets, for various types of cancers. Moreover, clinical and translational studies on anti-cancer drugs used to improve the efficacy of conservative therapies, to decrease the number of residual cancer cells after operation, and to maintain the quality of life in patients with cancer, are invited.

Assoc. Prof. Yasuyoshi Miyata
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Anti-Cancer therapy;
Promising target;
Conservative therapy;
Peri-operative therapy;
Natural product.

Published Papers (9 papers)

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Research

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15 pages, 1957 KiB

Open AccessArticle

Synthesis and Cytotoxic Analysis of Novel Myrtenyl Grafted Pseudo-Peptides Revealed Potential Candidates for Anticancer Therapy

by Odette Concepción, Julio Belmar, Alexander F. de la Torre, Francisco M. Muñiz, Mariano W. Pertino, Barbara Alarcón, Valeska Ormazabal, Estefania Nova-Lamperti, Felipe A. Zúñiga and Claudio A. Jiménez

Molecules 2020, 25(8), 1911; https://doi.org/10.3390/molecules25081911 - 21 Apr 2020

Cited by 6 | Viewed by 2866

Abstract

Myrtenal is a natural monoterpene isolated from essential oils of several plants and their derivates have shown to have several biological properties including cytotoxicity. The cytotoxic activity of these derivates are being investigated for their antitumor effect leading to the development of potential anticancer agents. In this study, novels Myrtenyl grafted pseudo-peptides were designed, synthesized and functionally characterized as possible therapeutic agents for cancer treatment. Thirteen novel Myrtenyl grafted pseudo-peptides were prepared in high atom economy and efficiency by a classic Ugi-4CR and sequential post-modification. Their structures were confirmed by NMR, and ESI-MS, and its cytotoxic activity was evaluated in three cancer cell lines and primary CD4+ T cells at different proliferative cycles. Our results revealed that some of these compounds showed significant cytotoxicity against human gastric, breast and colon adenocarcinoma cells lines, but not against human dermal fibroblast cell line. Moreover, from the thirteen novel myrtenyl synthesized the compound (1R,5S)-N-{[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-N-[2-(cyclohexylamino)-2–oxoethyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carboxamide (3b) proved to be the best candidate in terms of acceptable EC₅₀, and E_max values in cancer cell lines and at inducing cytotoxicity in CD4+ T cells undergoing active proliferation, without affecting non-proliferating T cells. Overall, the synthesis and characterization of our Myrtenyl derivates revealed novel potential anticancer candidates with selective cytotoxic activity. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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19 pages, 2813 KiB

Open AccessArticle

A New Hybrid δ-Lactone Induces Apoptosis and Potentiates Anticancer Activity of Taxol in HL-60 Human Leukemia Cells

by Katarzyna Gach-Janczak, Joanna Drogosz-Stachowicz, Angelika Długosz-Pokorska, Rafał Jakubowski, Tomasz Janecki, Jacek Szymański and Anna Janecka

Molecules 2020, 25(7), 1479; https://doi.org/10.3390/molecules25071479 - 25 Mar 2020

Cited by 4 | Viewed by 2561

Abstract

In the search for new drug candidates, researchers turn to natural substances isolated from plants which may be either used directly or may serve as a source for chemical modifications. An interesting strategy in the design of novel anticancer agents is based on the conjugation of two or more biologically active structural motifs into one hybrid compound. In this study, we investigated the anticancer potential of 4-benzyl-5,7-dimethoxy-4-methyl-3-methylidene-3,4-dihydro-2H-chroman-2-one (DL-247), a new hybrid molecule combining a chroman-2-one skeleton with an exo-methylidene bond conjugated with a carbonyl group, in human myeloid leukemia HL-60 cell line. The cytotoxicity of the new compound was tested using MTT assay. The effect of DL-247 on cell proliferation and apoptosis induction were studied by flow cytometry, fluorometric assay and ELISA analysis. DL-247 displayed high cytotoxic activity (IC₅₀ = 1.15 µM, after 24 h incubation), significantly inhibited cell proliferation and induced apoptosis by both, the intrinsic and extrinsic pathways. A combination of DL-247 with taxol exhibited a strong synergistic effect on DNA damage generation, apoptosis induction and inhibition of cell growth. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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14 pages, 3424 KiB

Open AccessArticle

Anti-Tumor Activity of Atractylenolide I in Human Colon Adenocarcinoma In Vitro

by Ka Woon Karen Chan, Hau Yin Chung and Wing Shing Ho

Molecules 2020, 25(1), 212; https://doi.org/10.3390/molecules25010212 - 04 Jan 2020

Cited by 12 | Viewed by 4606

Abstract

Atractylodes macrocephala is known to exhibit multi-arrays of biologic activity in vitro. However, detail of its anti-tumor activity is lacking. In this study, the effects of atractylenolide I (AT-I), a bio-active compound present in Atractylodes macrocephala rhizome was studied in the human colorectal adenocarcinoma cell line HT-29. The results showed that AT-I induced apoptosis of human colon cancer cells through activation of the mitochondria-dependent pathway. The IC₅₀ of AT-I was 277.6 μM, 95.7 μM and 57.4 μM, after 24, 48 and 72 h of incubation with HT-29, respectively. TUNEL and Annexin V-FITC/PI double stain assays showed HT-29 DNA fragmentation after cell treatment with various AT-I concentrations. Western blotting analysis revealed activation of both initiator and executioner caspases, including caspase 3, caspase 7, and caspase 9, as well as PARP, after HT-29 treatment with AT-I via downregulation of pro-survival Bcl-2, and upregulation of anti-survival Bcl-2 family proteins, including Bax, Bak, Bad, Bim, Bid and Puma. The studies show for the first time that AT-I is an effective drug candidate towards the HT-29 cell. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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19 pages, 3322 KiB

Open AccessArticle

Evaluation of Cyclic Peptide Inhibitors of the Grb7 Breast Cancer Target: Small Change in Cargo Results in Large Change in Cellular Activity

by Jianrong Sang, Ketav Kulkarni, Gabrielle M. Watson, Xiuquan Ma, David J. Craik, Sónia T. Henriques, Aaron G. Poth, Aurélie H. Benfield and Jacqueline A. Wilce

Molecules 2019, 24(20), 3739; https://doi.org/10.3390/molecules24203739 - 17 Oct 2019

Cited by 5 | Viewed by 3339

Abstract

Grb7 is an adapter protein, overexpressed in HER2+ve breast and other cancers, and identified as a therapeutic target. Grb7 promotes both proliferative and migratory cellular pathways through interaction of its SH2 domain with upstream binding partners including HER2, SHC, and FAK. Here we present the evaluation of a series of monocyclic and bicyclic peptide inhibitors that have been developed to specifically and potently target the Grb7 SH2-domain. All peptides tested were found to inhibit signaling in both ERK and AKT pathways in SKBR-3 and MDA-MB-231 cell lines. Proliferation, migration, and invasion assays revealed, however, that the second-generation bicyclic peptides were not more bioactive than the first generation G7-18NATE peptide, despite their higher in vitro affinity for the target. This was found not to be due to steric hindrance by the cell-permeability tag, as ascertained by ITC, but to differences in the ability of the bicyclic peptides to interact with and penetrate cellular membranes, as determined using SPR and mass spectrometry. These studies reveal that just small differences to amino acid composition can greatly impact the effectiveness of peptide inhibitors to their intracellular target and demonstrate that G7-18NATE remains the most effective peptide inhibitor of Grb7 developed to date. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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15 pages, 5208 KiB

Open AccessArticle

Zerumbone Induces Apoptosis in Breast Cancer Cells by Targeting αvβ3 Integrin upon Co-Administration with TP5-iRGD Peptide

by Eltayeb E. M. Eid, Abdulrahman S. Alanazi, Sanaz Koosha, Alian A. Alrasheedy, Faizul Azam, Ismail M. Taban, Habibullah Khalilullah, Mothanna Sadiq Al-Qubaisi and Mohammed A. Alshawsh

Molecules 2019, 24(14), 2554; https://doi.org/10.3390/molecules24142554 - 13 Jul 2019

Cited by 18 | Viewed by 3421

Abstract

Cell-penetrating peptides (CPPs) are highly promising tools to deliver therapeutic molecules into tumours. αVβ3 integrins are cell–matrix adhesion receptors, and are considered as an attractive target for anticancer therapies owing to their roles in the process of metastasis and angiogenesis. Therefore, this study aims to assess the effect of co-administration of zerumbone (ZER) and ZERencapsulated in hydroxypropyl-β-cyclodextrin with TP5-iRGD peptide towards cell cytotoxicity, apoptosis induction, and proliferation of normal and cancerous breast cells utilizing in vitro assays, as well as to study the molecular docking of ZER in complex with TP5-iRGD peptide. Cell viability assay findings indicated that ZER and ZERencapsulated in hydroxypropyl-β-cyclodextrin (ZER-HPβCD) inhibited the growth of estrogen receptor positivebreast cancer cells (ER⁺ MCF-7) at 72 h treatment with an inhibitory concentration (IC)₅₀ of 7.51 ± 0.2 and 5.08 ± 0.2 µg/mL, respectively, and inhibited the growth of triple negative breast cancer cells (MDA-MB-231) with an IC₅₀ of 14.96 ± 1.52 µg/mL and 12.18 ± 0.7 µg/mL, respectively. On the other hand, TP5-iRGD peptide showed no significant cytotoxicity on both cancer and normal cells. Interestingly, co-administration of TP5-iRGD peptide in MCF-7 cells reduced the IC₅₀ of ZER from 7.51 ± 0.2 µg/mL to 3.13 ± 0.7 µg/mL and reduced the IC₅₀ of ZER-HPβCD from 5.08 ± 0.2 µg/mL to 0.49 ± 0.004 µg/mL, indicating that the co-administration enhances the potency and increases the efficacy of ZER and ZER-HPβCD compounds. Acridine orange (AO)/propidium iodide (PI) staining under fluorescence microscopy showed evidence of early apoptosis after 72 h from the co-administration of ZER or ZER-HPβCD with TP5-iRGD peptide in MCF-7 breast cancer cells. The findings of the computational modelling experiment provide novel insights into the ZER interaction with integrin αvβ3 in the presence of TP5-iRGD, and this could explain why ZER has better antitumor activities when co-administered with TP5-iRGD peptide. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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18 pages, 4862 KiB

Open AccessArticle

The 3S Enantiomer Drives Enolase Inhibitory Activity in SF2312 and Its Analogues

by Federica Pisaneschi, Yu-Hsi Lin, Paul G. Leonard, Nikunj Satani, Victoria C. Yan, Naima Hammoudi, Sudhir Raghavan, Todd M. Link, Dimitra K. Georgiou, Barbara Czako and Florian L. Muller

Molecules 2019, 24(13), 2510; https://doi.org/10.3390/molecules24132510 - 09 Jul 2019

Cited by 7 | Viewed by 3968

Abstract

We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a racemic-diastereomeric mixture. However, co-crystal structures with Enolase 2 (ENO2) have consistently shown that only the (3S,5S)-enantiomer binds to the active site. The acidity of the alpha proton at C-3, which deprotonates under mildly alkaline conditions, results in racemization; thus while the separation of four enantiomeric intermediates was achieved via chiral High Performance Liquid Chromatography (HPLC) of the fully protected intermediate, deprotection inevitably nullified enantiopurity. To prevent epimerization of the C-3, we designed and synthesized MethylSF2312, ((1,5-dihydroxy-3-methyl-2-oxopyrrolidin-3-yl)phosphonic acid), which contains a fully-substituted C-3 alpha carbon. As a racemic-diastereomeric mixture, MethylSF2312 is equipotent to SF2312 in enzymatic and cellular systems against Enolase. Chiral HPLC separation of a protected MethylSF2312 precursor resulted in the efficient separation of the four enantiomers. After deprotection and inevitable re-equilibration of the anomeric C-5, (3S)-MethylSF2312 was up to 2000-fold more potent than (3R)-MethylSF2312 in an isolated enzymatic assay. This observation strongly correlates with biological activity in both human cancer cells and bacteria for the 3S enantiomer of SF2312. Novel X-ray structures of human ENO2 with chiral and racemic MethylSF2312 show that only (3S,5S)-enantiomer occupies the active site. Enolase inhibition is thus a direct result of binding by the (3S,5S)-enantiomer of MethylSF2312. Concurrent with these results for MethylSF2312, we contend that the (3S,5S)-SF2312 is the single active enantiomer of inhibitor SF2312. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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10 pages, 2020 KiB

Open AccessArticle

An Isoxazole Derivative SHU00238 Suppresses Colorectal Cancer Growth through miRNAs Regulation

by Haoyu Wang, Yurui Ma, Yifan Lin, Jiajie Liu, Rui Chen, Bin Xu and Yajun Liang

Molecules 2019, 24(12), 2335; https://doi.org/10.3390/molecules24122335 - 25 Jun 2019

Cited by 13 | Viewed by 3015

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116 cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC₅₀ (half maximal inhibitory concentration) of each derivative. Compound SHU00238, which was obtained by the copper nitrate-mediated [2+2+1] cycloaddition reaction of olefinic azlactone with naphthalene-1,4-dione, has a lower IC₅₀; we analyzed its inhibitory activity in further assays. Cell apoptosis was estimated by flow cytometry analysis in vitro. SHU00238 injection was used to treat tumor-bearing mice. We found that SHU00238 suppressed cell viability and promoted cell apoptosis in vitro. SHU00238 treatment significantly inhibited colonic tumor growth in vivo. Furthermore, we compared the miRNAs expression changes in HCT116 cells before and after SHU00238 treatment. MiRNA profiling revealed that SHU00238 treatment affected cell fate by regulating a set of miRNAs. In conclusion, SHU00238 impedes CRC tumor cell proliferation and promotes cell apoptosis by miRNAs regulation. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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13 pages, 2196 KiB

Open AccessArticle

Tissue Distribution and Anti-Lung Cancer Effect of 10-Hydroxycamptothecin Combined with Platycodonis Radix and Glycyrrhizae Radix ET Rhizoma

by Wugang Zhang, Mulan Li, Wendi Du, Wuliang Yang, Guofeng Li, Chen Zhang, Xinli Liang and Haifang Chen

Molecules 2019, 24(11), 2068; https://doi.org/10.3390/molecules24112068 - 30 May 2019

Cited by 12 | Viewed by 2861

Abstract

10-Hydroxycamptothecin (HCPT) is a broad-spectrum chemotherapeutic drug, although its side effects and multidrug resistance (MDR) limit its clinical application. A range of drug delivery systems have been utilized to overcome its shortcomings and maintain its therapeutic efficacy, however the use of the transport effect of traditional Chinese medicines (TCMs) to improve the distribution of chemotherapeutic drugs has not been widely reported. Platycodonis Radix (JG) and Glycyrrhizae Radix ET Rhizoma (GC) are common TCMs in clinics and are often combined as drug pairs to act as “transport agents”. In the present study, the effect of JG and GC (JGGC) on the distribution of HCPT in tissues and its antitumor efficacy after being combined as a therapy were investigated, for which ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used. Furthermore, the effect on the protein expression of multidrug resistance proteins (P-gp and LRP), and the immunomodulatory and synergistic antiapoptotic effect on Lewis lung cancer-bearing C57BL/6J mice were also evaluated. The results demonstrate that JGGC significantly increased the area under the concentration time curve (AUC) and mean residence time (MRT) and reduced the clearance rate (CL) of HCPT. In addition, the combined use of JGGC decreased the levels of LRP, P-gp and Bcl-2/Bax when treated with HCPT. JGGC also significantly elevated the levels of RBCs, PLTs, HGB, IL-2, and IFN-γ, and decreased IL-10 levels. In summary, an increased concentration of HCPT in tissues was observed when it was combined with JGGC through inhibition of efflux protein, with a synergistic enhancement of the anticancer effect observed through promotion of apoptosis and immunity due to a reversion of the Th1/Th2 shift. Our findings provide a reference for the feasibility of combining JGGC with chemotherapy drugs in clinical applications. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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Review

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16 pages, 2080 KiB

Open AccessReview

Penfluridol as a Candidate of Drug Repurposing for Anticancer Agent

by Nguyen Minh Tuan and Chang Hoon Lee

Molecules 2019, 24(20), 3659; https://doi.org/10.3390/molecules24203659 - 11 Oct 2019

Cited by 20 | Viewed by 6068

Abstract

Penfluridol has robust antipsychotic efficacy and is a first-generation diphenylbutylpiperidine. Its effects last for several days after a single oral dose and it can be administered once a week to provide better compliance and symptom control. Recently; strong antitumour effects for penfluridol were discovered in various cancer cell lines; such as breast; pancreatic; glioblastoma; and lung cancer cells via several distinct mechanisms. Therefore; penfluridol has drawn much attention as a potentially novel anti-tumour agent. In addition; the anti-cancer effects of penfluridol have been demonstrated in vivo: results showed slight changes in the volume and weight of organs at doses tested in animals. This paper outlines the potential for penfluridol to be developed as a next-generation anticancer drug. Full article

(This article belongs to the Special Issue Anti-Cancer Drug: Discovery, Development and Combination)

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