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Molecular Target and Action Mechanism of Anti-Cancer Agents

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

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 66725

Special Issue Editor

Special Issue Information

Dear Colleagues,

The idea of precision oncology is no longer new, but recent advances in functional genomics and proteomics are changing the way physicians and scientists approach the diagnosis of cancer risk as well as treatment. Although precision medicine is not yet part of routine care for most cancer patients, increased knowledge of cancer diagnosis with more detailed stratification based on patients’ genetic changes helps to move the field of precision oncology forward. Of course, developing new anticancer agents targeting genetic changes is another important part of precision oncology. In this context, this Special Issue aims to cover all areas of molecular-mechanism-based research for anticancer therapy. It welcomes original research, review articles, and short communications on specific molecular mechanisms of any anticancer agents, including conventional chemotherapy, novel potential anticancer drug candidates, and their combinations with any other anticancer modalities.

Prof. Dr. Seok-Geun Lee
Guest Editor

Manuscript Submission Information

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Keywords

  • cancer
  • conventional therapy
  • targeted therapy
  • immunotherapy
  • chemoprevention
  • molecular target
  • molecular mechanism
  • drug resistance
  • combinatorial therapy

Published Papers (19 papers)

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Editorial

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4 pages, 191 KiB  
Editorial
Molecular Target and Action Mechanism of Anti-Cancer Agents
by Seok-Geun Lee
Int. J. Mol. Sci. 2023, 24(9), 8259; https://doi.org/10.3390/ijms24098259 - 4 May 2023
Cited by 1 | Viewed by 1405
Abstract
Precision oncology, also known as personalized medicine, is an evolving approach to cancer treatment that aims to tailor therapies to individual patients based on their unique molecular profile, including genetic alterations and other biomarkers [...] Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)

Research

Jump to: Editorial, Review

12 pages, 2319 KiB  
Article
Imatinib Regulates miR-483-3p and Mitochondrial Respiratory Complexes in Gastrointestinal Stromal Tumors
by Wen-Kuan Huang, Hao Shi, Pinar Akçakaya, Katarina Zeljic, Anastasia Gangaev, Stefano Caramuta, Chun-Nan Yeh, Robert Bränström, Catharina Larsson and Weng-Onn Lui
Int. J. Mol. Sci. 2021, 22(19), 10600; https://doi.org/10.3390/ijms221910600 - 30 Sep 2021
Cited by 7 | Viewed by 1908
Abstract
Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the [...] Read more.
Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that miR-483-3p was one of the most downregulated miRNAs in imatinib-treated tumors compared to untreated tumors. Using an extended series of GIST samples, we further validated the downregulation of miR-483-3p in imatinib-treated GIST samples by RT-qPCR. Using both gain- and loss-of-function experiments, we showed that miR-483-3p could regulate mitochondrial respiratory Complex II expression, suggesting its role in OXPHOS regulation. Functionally, miR-483-3p overexpression could rescue imatinib-induced cell death. These findings provide the molecular link for imatinib-induced OXPHOS expression and the biological role of miR-483-3p in regulating cell viability upon imatinib treatment. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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21 pages, 6948 KiB  
Article
Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors
by Nils Goehringer, Bernhard Biersack, Yayi Peng, Rainer Schobert, Marco Herling, Andi Ma, Bianca Nitzsche and Michael Höpfner
Int. J. Mol. Sci. 2021, 22(16), 8432; https://doi.org/10.3390/ijms22168432 - 5 Aug 2021
Cited by 14 | Viewed by 2104
Abstract
New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor [...] Read more.
New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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29 pages, 25606 KiB  
Article
A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo
by Ana María Zárate, Christian Espinosa-Bustos, Simón Guerrero, Angélica Fierro, Felipe Oyarzún-Ampuero, Andrew F. G. Quest, Lucia Di Marcotullio, Elena Loricchio, Miriam Caimano, Andrea Calcaterra, Matías González-Quiroz, Adam Aguirre, Jaime Meléndez and Cristian O. Salas
Int. J. Mol. Sci. 2021, 22(16), 8372; https://doi.org/10.3390/ijms22168372 - 4 Aug 2021
Cited by 10 | Viewed by 2694
Abstract
The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, [...] Read more.
The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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14 pages, 32021 KiB  
Article
Promyelocytic Leukemia Proteins Regulate Fanconi Anemia Gene Expression
by Anudari Munkhjargal, Myung-Jin Kim, Da-Yeon Kim, Young-Jun Jeon, Young-Hoon Kee, Lark-Kyun Kim and Yong-Hwan Kim
Int. J. Mol. Sci. 2021, 22(15), 7782; https://doi.org/10.3390/ijms22157782 - 21 Jul 2021
Cited by 3 | Viewed by 2593
Abstract
Promyelocytic leukemia (PML) protein is the core component of subnuclear structures called PML nuclear bodies that are known to play important roles in cell survival, DNA damage responses, and DNA repair. Fanconi anemia (FA) proteins are required for repairing interstrand DNA crosslinks (ICLs). [...] Read more.
Promyelocytic leukemia (PML) protein is the core component of subnuclear structures called PML nuclear bodies that are known to play important roles in cell survival, DNA damage responses, and DNA repair. Fanconi anemia (FA) proteins are required for repairing interstrand DNA crosslinks (ICLs). Here we report a novel role of PML proteins, regulating the ICL repair pathway. We found that depletion of the PML protein led to the significant reduction of damage-induced FANCD2 mono-ubiquitination and FANCD2 foci formation. Consistently, the cells treated with siRNA against PML showed enhanced sensitivity to a crosslinking agent, mitomycin C. Further studies showed that depletion of PML reduced the protein expression of FANCA, FANCG, and FANCD2 via reduced transcriptional activity. Interestingly, we observed that damage-induced CHK1 phosphorylation was severely impaired in cells with depleted PML, and we demonstrated that CHK1 regulates FANCA, FANCG, and FANCD2 transcription. Finally, we showed that inhibition of CHK1 phosphorylation further sensitized cancer cells to mitomycin C. Taken together, these findings suggest that the PML is critical for damage-induced CHK1 phosphorylation, which is important for FA gene expression and for repairing ICLs. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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17 pages, 4714 KiB  
Article
Cytoprotective Effect of Vitamin D on Doxorubicin-Induced Cardiac Toxicity in Triple Negative Breast Cancer
by Kevin J Lee, Griffin Wright, Hannah Bryant, Leigh Ann Wiggins, Valeria L. Dal Zotto, Michele Schuler, Christopher Malozzi, Michael V Cohen and Natalie R Gassman
Int. J. Mol. Sci. 2021, 22(14), 7439; https://doi.org/10.3390/ijms22147439 - 12 Jul 2021
Cited by 16 | Viewed by 3422
Abstract
Background: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC [...] Read more.
Background: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. Methods: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. Results: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). Conclusions: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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19 pages, 5902 KiB  
Article
Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells
by Jang Mi Han, Jae Kyung Sohng, Woo-Haeng Lee, Tae-Jin Oh and Hye Jin Jung
Int. J. Mol. Sci. 2021, 22(5), 2473; https://doi.org/10.3390/ijms22052473 - 1 Mar 2021
Cited by 8 | Viewed by 2806
Abstract
We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in [...] Read more.
We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in proteome expression in AGS cells following compound 9 treatment were analyzed using two-dimensional gel electrophoresis (2-DE), followed by MALDI/TOF/MS. Analyses using chemical proteomics and western blotting revealed that compound 9 treatment significantly suppressed the expression of cyclophilin A (CypA), a member of the immunophilin family. Furthermore, compound 9 downregulated CD147-mediated mitogen-activated protein kinase (MAPK) signaling pathway, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) by inhibiting the expression of CD147, the cellular receptor of CypA. Notably, the responses of AGS cells to CypA knockdown were significantly correlated with the anticancer and antiangiogenic effects of compound 9. CypA siRNAs reduced the expression of CD147 and phosphorylation of JNK and ERK1/2. In addition, the suppressive effects of CypA siRNAs on proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. The specific interaction between compound 9 and CypA was also confirmed using the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) approaches. Moreover, in silico docking analysis revealed that the structure of compound 9 was a good fit for the cyclosporin A binding cavity of CypA. Collectively, these findings provide a novel molecular basis for compound 9-mediated suppression of gastric cancer progression through the targeting of CypA. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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19 pages, 4179 KiB  
Article
New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells
by Eva Schaller, Andi Ma, Lisa Chiara Gosch, Adrian Klefenz, David Schaller, Nils Goehringer, Leonard Kaps, Detlef Schuppan, Andrea Volkamer, Rainer Schobert, Bernhard Biersack, Bianca Nitzsche and Michael Höpfner
Int. J. Mol. Sci. 2021, 22(5), 2243; https://doi.org/10.3390/ijms22052243 - 24 Feb 2021
Cited by 9 | Viewed by 3694
Abstract
New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC50 values below that of the clinically [...] Read more.
New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC50 values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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14 pages, 3582 KiB  
Article
Activity-Based Protein Profiling Reveals Potential Dasatinib Targets in Gastric Cancer
by Kyoung-Min Choi, Eunji Cho, Geul Bang, Seong-Jae Lee, Boram Kim, Ji-Hee Kim, Seo-Gyu Park, Eun Hee Han, Young-Ho Chung, Jin Young Kim, Eunjung Kim and Jae-Young Kim
Int. J. Mol. Sci. 2020, 21(23), 9276; https://doi.org/10.3390/ijms21239276 - 4 Dec 2020
Cited by 9 | Viewed by 3404
Abstract
Dasatinib is a multi-target kinase inhibitor, whose targets include BCR-ABL, SRC family kinases, and various cancer kinases. The elevated SRC activity in gastric cancer (GC) has prompted the need for the therapeutic application of dasatinib in GC. We observed that the efficacy of [...] Read more.
Dasatinib is a multi-target kinase inhibitor, whose targets include BCR-ABL, SRC family kinases, and various cancer kinases. The elevated SRC activity in gastric cancer (GC) has prompted the need for the therapeutic application of dasatinib in GC. We observed that the efficacy of dasatinib varied with the GC cell lines. The differential effect of dasatinib was not correlated with the basal SRC activity of each cell line. Moreover, the GC cell lines showing the strong antitumor effects of dasatinib were refractory to other SRC inhibitors, i.e., bosutinib and saracatinib, suggesting that unexpected dasatinib’s targets could exist. To profile the targets of dasatinib in GC, we performed activity-based protein profiling (ABPP) via mass spectrometry using a desthiobiotin-ATP probe. We identified 29 and 18 kinases as potential targets in dasatinib-sensitive (SNU-216, MKN-1) and -resistant (SNU-484, SNU-601) cell lines, respectively. The protein–protein interaction mapping of the differential drug targets in dasatinib-sensitive and -resistant GC using the STRING database suggested that dasatinib could target cellular energy homeostasis in the drug-sensitive GC. RNAi screening for identified targets indicated p90RSK could be a novel dasatinib target, which is important for maintaining the viability and motility of GC cells. Further functional validation of dasatinib off-target actions will provide more effective therapeutic options for GC. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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15 pages, 2398 KiB  
Article
Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance
by Sol-Bi Shin, Chang-Hyeon Kim, Hay-Ran Jang and Hyungshin Yim
Int. J. Mol. Sci. 2020, 21(22), 8629; https://doi.org/10.3390/ijms21228629 - 16 Nov 2020
Cited by 17 | Viewed by 3122
Abstract
USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high [...] Read more.
USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels of USP7, especially in taxane-resistant cancer. USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix. Depletion of USP7 induced multiple spindle pole formation in mitosis, and, consequently, resulted in mitotic catastrophe. When USP7 was blocked in the paclitaxel-resistant lung cancer NCI-H460TXR cells, which has resistance to mitotic catastrophe, NCI-H460TXR cells underwent apoptosis effectively. Furthermore, combination treatment with the mitotic kinase PLK1 inhibitor volasertib and the USP7 inhibitor P22077 showed a strong synergism through down-regulation of MDR1/ABCB1 in paclitaxel-resistant lung cancer. Therefore, we suggest USP7 is a promising target for cancer therapy, and combination therapy with inhibitors of PLK1 and USP7 may be valuable for treating paclitaxel-resistant cancers, because of their strong synergism. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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13 pages, 2606 KiB  
Article
Anti-neoplastic Effect of Ginkgolide C through Modulating c-Met Phosphorylation in Hepatocellular Carcinoma Cells
by Min Hee Yang, Seung Ho Baek, Jae-Young Um and Kwang Seok Ahn
Int. J. Mol. Sci. 2020, 21(21), 8303; https://doi.org/10.3390/ijms21218303 - 5 Nov 2020
Cited by 18 | Viewed by 2521
Abstract
Ginkgolide C (GGC) derived from Ginkgo biloba, has been reported to exhibit various biological functions. However, the anti-neoplastic effect of GGC and its mechanisms in liver cancer have not been studied previously. Hepatocyte growth factor (HGF)/c-mesenchymal–epithelial transition receptor (c-Met) pathway can regulate [...] Read more.
Ginkgolide C (GGC) derived from Ginkgo biloba, has been reported to exhibit various biological functions. However, the anti-neoplastic effect of GGC and its mechanisms in liver cancer have not been studied previously. Hepatocyte growth factor (HGF)/c-mesenchymal–epithelial transition receptor (c-Met) pathway can regulate tumor growth and metastasis in hepatocellular carcinoma (HCC) cells. This study aimed to evaluate the anti-neoplastic effect of GGC against HCC cells and we observed that GGC inhibited HGF-induced c-Met and c-Met downstream oncogenic pathways, such as PI3K/Akt/mTOR and MEK/ERK. In addition, GGC also suppressed the proliferation of expression of diverse tumorigenic proteins (Bcl-2, Bcl-xL, Survivin, IAP-1, IAP-2, Cyclin D1, and COX-2) and induced apoptosis. Interestingly, the silencing of c-Met by small interfering RNA (siRNA) mitigated c-Met expression and enhanced GGC-induced apoptosis. Moreover, it was noted that GGC also significantly reduced the invasion and migration of HCC cells. Overall, the data clearly demonstrate that GGC exerts its anti-neoplastic activity through modulating c-Met phosphorylation and may be used as an effective therapy against HCC. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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Review

Jump to: Editorial, Research

26 pages, 4019 KiB  
Review
Insights into the Mechanisms of Action of MDA-7/IL-24: A Ubiquitous Cancer-Suppressing Protein
by Jinkal Modi, Abhishek Roy, Anjan K. Pradhan, Amit Kumar, Sarmistha Talukdar, Praveen Bhoopathi, Santanu Maji, Padmanabhan Mannangatti, Daniel Sanchez De La Rosa, Jiong Li, Chunqing Guo, Mark A. Subler, Jolene J. Windle, Webster K. Cavenee, Devanand Sarkar, Xiang-Yang Wang, Swadesh K. Das, Luni Emdad and Paul B. Fisher
Int. J. Mol. Sci. 2022, 23(1), 72; https://doi.org/10.3390/ijms23010072 - 22 Dec 2021
Cited by 4 | Viewed by 4191
Abstract
Melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24), a secreted protein of the IL-10 family, was first identified more than two decades ago as a novel gene differentially expressed in terminally differentiating human metastatic melanoma cells. MDA-7/IL-24 functions as a potent tumor suppressor exerting a diverse [...] Read more.
Melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24), a secreted protein of the IL-10 family, was first identified more than two decades ago as a novel gene differentially expressed in terminally differentiating human metastatic melanoma cells. MDA-7/IL-24 functions as a potent tumor suppressor exerting a diverse array of functions including the inhibition of tumor growth, invasion, angiogenesis, and metastasis, and induction of potent “bystander” antitumor activity and synergy with conventional cancer therapeutics. MDA-7/IL-24 induces cancer-specific cell death through apoptosis or toxic autophagy, which was initially established in vitro and in preclinical animal models in vivo and later in a Phase I clinical trial in patients with advanced cancers. This review summarizes the history and our current understanding of the molecular/biological mechanisms of MDA-7/IL-24 action rendering it a potent cancer suppressor. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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60 pages, 3739 KiB  
Review
Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?
by Yong Weon Yi, Kyu Sic You, Jeong-Soo Park, Seok-Geun Lee and Yeon-Sun Seong
Int. J. Mol. Sci. 2022, 23(1), 48; https://doi.org/10.3390/ijms23010048 - 21 Dec 2021
Cited by 39 | Viewed by 5522
Abstract
Ribosomal protein S6 (RPS6) is a component of the 40S small ribosomal subunit and participates in the control of mRNA translation. Additionally, phospho (p)-RPS6 has been recognized as a surrogate marker for the activated PI3K/AKT/mTORC1 pathway, which occurs in many cancer types. However, [...] Read more.
Ribosomal protein S6 (RPS6) is a component of the 40S small ribosomal subunit and participates in the control of mRNA translation. Additionally, phospho (p)-RPS6 has been recognized as a surrogate marker for the activated PI3K/AKT/mTORC1 pathway, which occurs in many cancer types. However, downstream mechanisms regulated by RPS6 or p-RPS remains elusive, and the therapeutic implication of RPS6 is underappreciated despite an approximately half a century history of research on this protein. In addition, substantial evidence from RPS6 knockdown experiments suggests the potential role of RPS6 in maintaining cancer cell proliferation. This motivates us to investigate the current knowledge of RPS6 functions in cancer. In this review article, we reviewed the current information about the transcriptional regulation, upstream regulators, and extra-ribosomal roles of RPS6, with a focus on its involvement in cancer. We also discussed the therapeutic potential of RPS6 in cancer. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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29 pages, 4627 KiB  
Review
Platinum and Palladium Complexes as Promising Sources for Antitumor Treatments
by Robert Czarnomysy, Dominika Radomska, Olga Klaudia Szewczyk, Piotr Roszczenko and Krzysztof Bielawski
Int. J. Mol. Sci. 2021, 22(15), 8271; https://doi.org/10.3390/ijms22158271 - 31 Jul 2021
Cited by 47 | Viewed by 4374
Abstract
There is a need for new, safer, and more effective agents to treat cancer. Cytostatics that have transition metals at their core have attracted renewed interest from scientists. Researchers are attempting to use chemotherapeutics, such as cisplatin, in combination therapy (i.e., in order [...] Read more.
There is a need for new, safer, and more effective agents to treat cancer. Cytostatics that have transition metals at their core have attracted renewed interest from scientists. Researchers are attempting to use chemotherapeutics, such as cisplatin, in combination therapy (i.e., in order to enhance their effectiveness). Moreover, studies are being carried out to modify molecules, by developing them into multinuclear structures, linking different compounds to commonly used drugs, or encapsulating them in nanoparticles to improve pharmacokinetic parameters, and increase the selectivity of these drugs. Therefore, we attempted to organize recent drug findings that contain palladium and platinum atoms in their structures. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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20 pages, 3059 KiB  
Review
MicroRNAs and Long Noncoding RNAs as Novel Therapeutic Targets in Estrogen Receptor-Positive Breast and Ovarian Cancers
by Tushar Singh Barwal, Uttam Sharma, Sonali Bazala, Ipsa Singh, Manju Jain, Hridayesh Prakash, Shashank Shekhar, Elise N. Sandberg, Anupam Bishayee and Aklank Jain
Int. J. Mol. Sci. 2021, 22(8), 4072; https://doi.org/10.3390/ijms22084072 - 15 Apr 2021
Cited by 10 | Viewed by 3289
Abstract
Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have shown to prevent metastasis and angiogenesis in estrogen receptor (ER)-positive breast and ovarian tumors. They function primarily by reducing estrogen production in ER-positive post-menopausal breast and ovarian cancer patients. Unfortunately, current AI-based therapies [...] Read more.
Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have shown to prevent metastasis and angiogenesis in estrogen receptor (ER)-positive breast and ovarian tumors. They function primarily by reducing estrogen production in ER-positive post-menopausal breast and ovarian cancer patients. Unfortunately, current AI-based therapies often have detrimental side-effects, along with acquired resistance, with increased cancer recurrence. Thus, there is an urgent need to identify novel AIs with fewer side effects and improved therapeutic efficacies. In this regard, we and others have recently suggested noncoding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), as potential molecular targets for utilization in modulating cancer hallmarks and overcoming drug resistance in several cancers, including ER-positive breast and ovarian cancer. Herein, we describe the disruptive functions of several miRNAs and lncRNAs seen in dysregulated cancer metabolism, with a focus on the gene encoding for aromatase (CYP19A1 gene) and estrogen synthesis as a novel therapeutic approach for treating ER-positive breast and ovarian cancers. Furthermore, we discuss the oncogenic and tumor-suppressive roles of several miRNAs (oncogenic miRNAs: MIR125b, MIR155, MIR221/222, MIR128, MIR2052HG, and MIR224; tumor-suppressive miRNAs: Lethal-7f, MIR27B, MIR378, and MIR98) and an oncogenic lncRNA (MIR2052HG) in aromatase-dependent cancers via transcriptional regulation of the CYP19A1 gene. Additionally, we discuss the potential effects of dysregulated miRNAs and lncRNAs on the regulation of critical oncogenic molecules, such as signal transducer, and activator of transcription 3, β-catenin, and integrins. The overall goal of this review is to stimulate further research in this area and to facilitate the development of ncRNA-based approaches for more efficacious treatments of ER-positive breast and ovarian cancer patients, with a slight emphasis on associated treatment–delivery mechanisms. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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17 pages, 346 KiB  
Review
The Importance of Tumor Stem Cells in Glioblastoma Resistance to Therapy
by Vincenzo Mattei, Francesca Santilli, Stefano Martellucci, Simona Delle Monache, Jessica Fabrizi, Alessandro Colapietro, Adriano Angelucci and Claudio Festuccia
Int. J. Mol. Sci. 2021, 22(8), 3863; https://doi.org/10.3390/ijms22083863 - 8 Apr 2021
Cited by 33 | Viewed by 3654
Abstract
Glioblastoma (GBM) is known to be the most common and lethal primary malignant brain tumor. Therapies against this neoplasia have a high percentage of failure, associated with the survival of self-renewing glioblastoma stem cells (GSCs), which repopulate treated tumors. In addition, despite new [...] Read more.
Glioblastoma (GBM) is known to be the most common and lethal primary malignant brain tumor. Therapies against this neoplasia have a high percentage of failure, associated with the survival of self-renewing glioblastoma stem cells (GSCs), which repopulate treated tumors. In addition, despite new radical surgery protocols and the introduction of new anticancer drugs, protocols for treatment, and technical advances in radiotherapy, no significant improvement in the survival rate for GBMs has been realized. Thus, novel antitarget therapies could be used in conjunction with standard radiochemotherapy approaches. Targeted therapy, indeed, may address specific targets that play an essential role in the proliferation, survival, and invasiveness of GBM cells, including numerous molecules involved in signal transduction pathways. Significant cellular heterogeneity and the hierarchy with GSCs showing a therapy-resistant phenotype could explain tumor recurrence and local invasiveness and, therefore, may be a target for new therapies. Therefore, the forced differentiation of GSCs may be a promising new approach in GBM treatment. This article provides an updated review of the current standard and experimental therapies for GBM, as well as an overview of the molecular characteristics of GSCs, the mechanisms that activate resistance to current treatments, and a new antitumor strategy for treating GSCs for use as therapy. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
27 pages, 1695 KiB  
Review
Selenium Compounds as Novel Potential Anticancer Agents
by Dominika Radomska, Robert Czarnomysy, Dominik Radomski and Krzysztof Bielawski
Int. J. Mol. Sci. 2021, 22(3), 1009; https://doi.org/10.3390/ijms22031009 - 20 Jan 2021
Cited by 85 | Viewed by 4697
Abstract
The high number of new cancer incidences and the associated mortality continue to be alarming, leading to the search for new therapies that would be more effective and less burdensome for patients. As there is evidence that Se compounds can have chemopreventive activity, [...] Read more.
The high number of new cancer incidences and the associated mortality continue to be alarming, leading to the search for new therapies that would be more effective and less burdensome for patients. As there is evidence that Se compounds can have chemopreventive activity, studies have begun to establish whether these compounds can also affect already existing cancers. This review aims to discuss the different classes of Se-containing compounds, both organic and inorganic, natural and synthetic, and the mechanisms and molecular targets of their anticancer activity. The chemical classes discussed in this paper include inorganic (selenite, selenate) and organic compounds, such as diselenides, selenides, selenoesters, methylseleninic acid, 1,2-benzisoselenazole-3[2H]-one and selenophene-based derivatives, as well as selenoamino acids and Selol. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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13 pages, 711 KiB  
Review
Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules
by Christos Vallilas, Panagiotis Sarantis, Anastasios Kyriazoglou, Evangelos Koustas, Stamatios Theocharis, Athanasios G. Papavassiliou and Michalis V. Karamouzis
Int. J. Mol. Sci. 2021, 22(2), 493; https://doi.org/10.3390/ijms22020493 - 6 Jan 2021
Cited by 35 | Viewed by 5458
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, [...] Read more.
Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors). Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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15 pages, 579 KiB  
Review
The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL
by Aristofania Simatou, Panagiotis Sarantis, Evangelos Koustas, Athanasios G. Papavassiliou and Michalis V. Karamouzis
Int. J. Mol. Sci. 2020, 21(20), 7570; https://doi.org/10.3390/ijms21207570 - 14 Oct 2020
Cited by 18 | Viewed by 4027
Abstract
The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis. Additionally, the RANKL/RANK axis is a significant mediator of progesterone-driven mammary epithelial cell proliferation, potentially contributing to breast cancer initiation [...] Read more.
The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis. Additionally, the RANKL/RANK axis is a significant mediator of progesterone-driven mammary epithelial cell proliferation, potentially contributing to breast cancer initiation and progression. Moreover, several studies supported the synergistic effect of RANK and epidermal growth factor receptor (EGFR) and described RANK’s involvement in epidermal growth factor receptor 2 (ERBB2)-positive carcinogenesis. Consequently, anti-RANKL treatment has been proposed as a new approach to preventing and treating breast cancer and metastases. Recently, RANKL/RANK signaling pathway inhibition has been shown to modulate the immune environment and enhance the efficacy of anti-CTLA-4 and anti-PD-1 monoclonal antibodies against solid tumors. Clinical and experimental trials have emerged evaluating RANKL inhibition as an enhancer of the immune response, rendering resistant tumors responsive to immune therapies. Trials evaluating the combinatorial effect of immune checkpoint inhibitors and anti-RANKL treatment in double-positive (RANK+/ERBB2+) patients are encouraging. Full article
(This article belongs to the Special Issue Molecular Target and Action Mechanism of Anti-Cancer Agents)
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