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Cancers
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Molecular Mechanisms of Anti-Cancer Drugs Action
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Molecular Mechanisms of Anti-Cancer Drugs Action

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Drug Development".

Deadline for manuscript submissions: closed (30 May 2024) | Viewed by 11344

Special Issue Editor

Dr. Barbara Pucelik

E-Mail Website
Guest Editor
Małopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland
Interests: photodynamic therapy, drug design, immunotherapy, nanotechnology, targeted drugs, personalized medicine, stem cells, 3D models

Special Issue Information

Dear Colleagues,

Cancer is one of the leading causes of death worldwide. Despite the huge advances in diagnosis and treatment, several cancers still have poor prognoses, and traditional treatments, such as chemo- or radiotherapy, are quite invasive and not always effective.

In recent decades, the most important clinical improvements in anticancer drugs have occurred with the debut of treatments with novel mechanisms of action. Researchers have also learned that the microenvironment in which different cancers start, grow, and thrive are not always the same. Tumor heterogeneity is the main cause of drug resistance leading to therapeutic failure. Because drug resistance occurs through different mechanisms due to genetic, epigenetic, and phenotypic heterogeneity, understanding the mechanisms of anticancer drugd, as well as the design and development of improved or novel targeted drugs with unique modes of action, is urgently needed.

Understanding the factors that affect cancer resistance to these agents can provide important new insights into whether a particular drug is likely to be effective in cancer treatment or not. Moreover, modeling the interaction of anticancer drugs in silico as well as improving innovative drug delivery systems may certainly lead to identification of relevant variables and lead to precise and effective treatment design with unprecedented benefit for cancer patients.

This Special Issue will highlight recent advances and strategies in the mechanisms of action of anticancer drugs: from in silico design to synthesis to biological activity. It will cover the role of (potential) drugs in overcoming drug resistance and major limitations of traditional treatments. Thereby, we are pleased to invite you to submit research articles, short communications, and systematic reviews that will bring significant contributions to this topic.

We look forward to receiving your valuable contributions.

Dr. Barbara Pucelik
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 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. Cancers 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 2900 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

  • anticancer drug
  • drug interactions
  • medicinal chemistry
  • molecular mechanisms
  • anticancer activity
  • drug design
  • drug targeting
  • personalized medicine
  • targeted therapies
  • drug delivery

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (5 papers)

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Research

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18 pages, 2419 KiB  
Article
Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal
by Mariusz L. Hartman, Paulina Koziej, Katarzyna Kluszczyńska and Małgorzata Czyz
Cancers 2023, 15(19), 4799; https://doi.org/10.3390/cancers15194799 - 29 Sep 2023
Viewed by 1236
Abstract
Background: Although BRAFV600/MEK inhibitors improved the treatment of melanoma patients, resistance is acquired almost inevitably. Methods: Trametinib withdrawal/rechallenge and MCL-1 inhibition in trametinib-resistance models displaying distinct p-ERK1/2 levels were investigated. Results: Trametinib withdrawal/rechallenge caused reversible changes in ERK1/2 activity impacting the [...] Read more.
Background: Although BRAFV600/MEK inhibitors improved the treatment of melanoma patients, resistance is acquired almost inevitably. Methods: Trametinib withdrawal/rechallenge and MCL-1 inhibition in trametinib-resistance models displaying distinct p-ERK1/2 levels were investigated. Results: Trametinib withdrawal/rechallenge caused reversible changes in ERK1/2 activity impacting the balance between pro-survival and pro-apoptotic proteins. Reversible alterations were found in MCL-1 levels and MCL-1 inhibitors, BIM and NOXA. Taking advantage of melanoma cell dependency on MCL-1 for survival, we used S63845. While it was designed to inhibit MCL-1 activity, we showed that it also significantly reduced NOXA levels. S63845-induced apoptosis was detected as the enhancement of Annexin V-positivity, caspase-3/7 activation and histone H2AX phosphorylation. Percentages of Annexin V-positive cells were increased most efficiently in trametinib-resistant melanoma cells displaying the p-ERK1/2low/MCL-1low/BIMhigh/NOXAlow phenotype with EC50 values at concentrations as low as 0.1 μM. Higher ERK1/2 activity associated with increased MCL-1 level and reduced BIM level limited pro-apoptotic activity of S63845 further influenced by a NOXA level. Conclusions: Our study supports the notion that the efficiency of an agent designed to target a single protein can largely depend on the phenotype of cancer cells. Thus, it is important to define appropriate phenotype determinants to stratify the patients for the novel therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Anti-Cancer Drugs Action)
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10 pages, 866 KiB  
Article
A Multicenter, Open-Label, Phase I/II Study of FN-1501 in Patients with Advanced Solid Tumors
by Gary Edward Richardson, Raed Al-Rajabi, Dipesh Uprety, Anis Hamid, Stephen K. Williamson, Joaquina Baranda, Hirva Mamdani, Ya-Li Lee, Nitika, Li Li, Xingli Wang and Xunwei Dong
Cancers 2023, 15(9), 2553; https://doi.org/10.3390/cancers15092553 - 29 Apr 2023
Cited by 2 | Viewed by 2055
Abstract
Background: FN-1501, a potent inhibitor of receptor FMS-like tyrosine kinase 3 (FLT3) and CDK4/6, KIT, PDGFR, VEGFR2, ALK, and RET tyrosine kinase proteins, has demonstrated significant in vivo activity in various solid tumor and leukemia human xenograft [...] Read more.
Background: FN-1501, a potent inhibitor of receptor FMS-like tyrosine kinase 3 (FLT3) and CDK4/6, KIT, PDGFR, VEGFR2, ALK, and RET tyrosine kinase proteins, has demonstrated significant in vivo activity in various solid tumor and leukemia human xenograft models. Anomalies in FLT3 have an established role as a therapeutic target where the gene has been shown to play a critical role in the growth, differentiation, and survival of various cell types in hematopoietic cancer and have shown promise in various solid tumors. An open-label, Phase I/II study (NCT03690154) was designed to evaluate the safety and PK profile of FN-1501 as monotherapy in patients (pts) with advanced solid tumors and relapsed, refractory (R/R) AML. Methods: Pts received FN-1501 IV three times a week for 2 weeks, followed by 1 week off treatment in continuous 21-day cycles. Dose escalation followed a standard 3 + 3 design. Primary objectives include the determination of the maximum tolerated dose (MTD), safety, and recommended Phase 2 dose (RP2D). Secondary objectives include pharmacokinetics (PK) and preliminary anti-tumor activity. Exploratory objectives include the relationship between pharmacogenetic mutations (e.g., FLT3, TP53, KRAS, NRAS, etc.), safety, and efficacy; as well as an evaluation of the pharmacodynamic effects of treatment with FN-1501. Dose expansion at RP2D further explored the safety and efficacy of FN-1501 in this treatment setting. Results: A total of 48 adult pts with advanced solid tumors (N = 47) and AML (N = 1) were enrolled at doses ranging from 2.5 to 226 mg IV three times a week for two weeks in 21-day cycles (2 weeks on and 1 week off treatment). The median age was 65 years (range 30–92); 57% were female and 43% were male. The median number of prior lines of treatment was 5 (range 1–12). Forty patients evaluable for dose-limiting toxicity (DLT) assessment had a median exposure of 9.5 cycles (range 1–18 cycles). Treatment-related adverse events (TRAEs) were reported for 64% of the pts. The most common treatment-emergent adverse events (TEAEs), defined as those occurring in ≥20% of pts, primarily consisted of reversible Grade 1–2 fatigue (34%), nausea (32%), and diarrhea (26%). The most common Grade ≥3 events occurring in ≥5% of pts consisted of diarrhea and hyponatremia. Dose escalation was discontinued due to DLTs of Grade 3 thrombocytopenia (N = 1) and Grade 3 infusion-related reaction (N = 1) occurring in 2 pts. The maximum tolerated dose (MTD) was determined to be 170 mg. Conclusions: FN-1501 demonstrated reasonable safety, tolerability, and preliminary activity against solid tumors in doses up to 170 mg. Dose escalation was terminated based on 2 DLTs occurring at the 226 mg dose level. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Anti-Cancer Drugs Action)
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23 pages, 8651 KiB  
Article
Vemurafenib and Dabrafenib Downregulates RIPK4 Level
by Ewelina Madej, Anna A. Brożyna, Agnieszka Adamczyk, Norbert Wronski, Agnieszka Harazin-Lechowska, Anna Muzyk, Krzysztof Makuch, Michal Markiewicz, Janusz Rys and Agnieszka Wolnicka-Glubisz
Cancers 2023, 15(3), 918; https://doi.org/10.3390/cancers15030918 - 1 Feb 2023
Cited by 6 | Viewed by 2927
Abstract
Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular [...] Read more.
Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular targets are sought that could completely inhibit melanoma progression. Since receptor-interacting protein kinase (RIPK4) probably functions as an oncogene in melanoma and its structure is similar to the BRAF protein, we analyzed the impact of vemurafenib and dabrafenib on RIPK4 in melanomas. The in silico study confirmed the high similarity of BRAF kinase domains to the RIPK4 protein at both the sequence and structural levels and suggests that BRAFi could directly bind to RIPK4 even more strongly than to ATP. Furthermore, BRAFi inhibited ERK1/2 activity and lowered RIPK4 protein levels in BRAF-mutated melanoma cells (A375 and WM266.4), while in wild-type BRAF cells (BLM and LoVo), both inhibitors decreased the level of RIPK4 and enhanced ERK1/2 activity. The phosphorylation of phosphatidylethanolamine binding protein 1 (PEBP1)—a suppressor of the BRAF/MEK/ERK pathway—via RIPK4 observed in pancreatic cancer did not occur in melanoma. Neither downregulation nor upregulation of RIPK4 in BRAF- mutated cells affected PEBP1 levels or the BRAF/MEK/ERK pathway. The downregulation of RIPK4 inhibited cell proliferation and the FAK/AKT pathway, and increased BRAFi efficiency in WM266.4 cells. However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Anti-Cancer Drugs Action)
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Review

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32 pages, 3446 KiB  
Review
Modulation of Notch Signaling by Small-Molecular Compounds and Its Potential in Anticancer Studies
by Arkadiusz Czerwonka, Joanna Kałafut and Matthias Nees
Cancers 2023, 15(18), 4563; https://doi.org/10.3390/cancers15184563 - 14 Sep 2023
Cited by 3 | Viewed by 1950
Abstract
Notch signaling is responsible for conveying messages between cells through direct contact, playing a pivotal role in tissue development and homeostasis. The modulation of Notch-related processes, such as cell growth, differentiation, viability, and cell fate, offer opportunities to better understand and prevent disease [...] Read more.
Notch signaling is responsible for conveying messages between cells through direct contact, playing a pivotal role in tissue development and homeostasis. The modulation of Notch-related processes, such as cell growth, differentiation, viability, and cell fate, offer opportunities to better understand and prevent disease progression, including cancer. Currently, research efforts are mainly focused on attempts to inhibit Notch signaling in tumors with strong oncogenic, gain-of-function (GoF) or hyperactivation of Notch signaling. The goal is to reduce the growth and proliferation of cancer cells, interfere with neo-angiogenesis, increase chemosensitivity, potentially target cancer stem cells, tumor dormancy, and invasion, and induce apoptosis. Attempts to pharmacologically enhance or restore disturbed Notch signaling for anticancer therapies are less frequent. However, in some cancer types, such as squamous cell carcinomas, preferentially, loss-of-function (LoF) mutations have been confirmed, and restoring but not blocking Notch functions may be beneficial for therapy. The modulation of Notch signaling can be performed at several key levels related to NOTCH receptor expression, translation, posttranslational (proteolytic) processing, glycosylation, transport, and activation. This further includes blocking the interaction with Notch-related nuclear DNA transcription. Examples of small-molecular chemical compounds, that modulate individual elements of Notch signaling at the mentioned levels, have been described in the recent literature. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Anti-Cancer Drugs Action)
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24 pages, 2122 KiB  
Review
Potential Role of Carbon Nanomaterials in the Treatment of Malignant Brain Gliomas
by Maria Caffo, Antonello Curcio, Kumar Rajiv, Gerardo Caruso, Mario Venza and Antonino Germanò
Cancers 2023, 15(9), 2575; https://doi.org/10.3390/cancers15092575 - 30 Apr 2023
Cited by 7 | Viewed by 2210
Abstract
Malignant gliomas are the most common primary brain tumors in adults up to an extent of 78% of all primary malignant brain tumors. However, total surgical resection is almost unachievable due to the considerable infiltrative ability of glial cells. The efficacy of current [...] Read more.
Malignant gliomas are the most common primary brain tumors in adults up to an extent of 78% of all primary malignant brain tumors. However, total surgical resection is almost unachievable due to the considerable infiltrative ability of glial cells. The efficacy of current multimodal therapeutic strategies is, furthermore, limited by the lack of specific therapies against malignant cells, and, therefore, the prognosis of these in patients is still very unfavorable. The limitations of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agent to brain tumors, are major reasons for this unsolved clinical problem. The major problem in brain drug delivery is the presence of the blood–brain barrier, which limits the delivery of many chemotherapeutic agents. Nanoparticles, thanks to their chemical configuration, are able to go through the blood–brain barrier carrying drugs or genes targeted against gliomas. Carbon nanomaterials show distinct properties including electronic properties, a penetrating capability on the cell membrane, high drug-loading and pH-dependent therapeutic unloading capacities, thermal properties, a large surface area, and easy modification with molecules, which render them as suitable candidates for deliver drugs. In this review, we will focus on the potential effectiveness of the use of carbon nanomaterials in the treatment of malignant gliomas and discuss the current progress of in vitro and in vivo researches of carbon nanomaterials-based drug delivery to brain. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Anti-Cancer Drugs Action)
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