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Pharmaceuticals
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Advances in Cancer Treatment and Toxicity
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Advances in Cancer Treatment and Toxicity

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (10 March 2026) | Viewed by 5713

Special Issue Editor

Prof. Dr. Dinender K. Singla

E-Mail Website
Guest Editor
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
Interests: inflammation; heart; macrophages; cell death; doxorubicin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer drugs are commonly used to treat tumors. Unfortunately, most cancer drugs (doxorubicin, ponatinib, cisplatin, etc.) induce cardiomyopathy and muscle weakness as a side effect. The exact mechanisms of action of these drugs are far from clear; however, based on current research, it has been suggested that increased oxidative stress, inflammation, mitochondrial dysfunction and cell death are the prominent mechanisms involved in the development as well as progression of these diseases. Recent data suggest that researchers are investigating various therapeutic approaches, such as miRNA technology, antioxidative as well as anti-inflammatory drugs, antiapoptotic therapeutic options, cell therapy and exosomes.

Pharmaceuticals is organizing a Special Issue on the topic of cancer drug toxicity and interventions. In this Special Issue, we invite both original and review articles that cover the current concepts of anticancer-drug-induced toxicity in the heart and muscles. These articles can be of a wider scope, including topics such as oxidative stress, cell signaling, cell death, tissue remodeling, inflammation and other relevant molecular mechanisms that are involved in anticancer-drug-induced cardiac and muscle toxicity. We also welcome any current therapeutic strategies being investigated to attenuate anticancer-drug-induced side effects.

Prof. Dr. Dinender K. Singla
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 250 words) can be sent to the Editorial Office for assessment.

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. Pharmaceuticals is an international peer-reviewed open access monthly 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

  • oxidative stress
  • cell signaling
  • cell death
  • tissue remodeling
  • inflammation
  • molecular mechanisms
  • heart
  • muscle
  • antioxidants
  • cell therapy
  • exosomes

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Published Papers (5 papers)

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Research

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23 pages, 4593 KB  
Article
Integrated Omics Approach to Delineate the Mechanisms of Doxorubicin-Induced Cardiotoxicity
by Mohamed S. Dabour, Ibrahim Y. Abdelgawad, Bushra Sadaf, Mary R. Daniel, Marianne K. O. Grant, Anne H. Blaes, Pamala A. Jacobson and Beshay N. Zordoky
Pharmaceuticals 2026, 19(2), 234; https://doi.org/10.3390/ph19020234 - 29 Jan 2026
Viewed by 1213
Abstract
Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent whose clinical utility is limited by cardiotoxicity. To investigate underlying mechanisms, we employed a multi-omics approach integrating transcriptomics and proteomics, leveraging established mouse models of chronic DOX-induced cardiotoxicity. Methods: Five-week-old male mice received weekly [...] Read more.
Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent whose clinical utility is limited by cardiotoxicity. To investigate underlying mechanisms, we employed a multi-omics approach integrating transcriptomics and proteomics, leveraging established mouse models of chronic DOX-induced cardiotoxicity. Methods: Five-week-old male mice received weekly DOX (4 mg/kg) or saline injections for six weeks, with heart tissues harvested 4 days post-treatment. Differentially expressed genes (DEGs) and proteins (DEPs) were identified by bulk RNA-seq and proteomics, validated via qPCR and Western blot, respectively. Key DEPs were validated in plasma samples from DOX-treated breast cancer patients. Additionally, temporal comparison was conducted between DEPs in the mice hearts 4 days and 6 weeks post-DOX. Results: RNA-seq revealed upregulation of stress-responsive genes (Phlda3, Trp53inp1) and circadian regulators (Nr1d1), with downregulation of Apelin and Cd74. Proteomics identified upregulation of serpina3n, thrombospondin-1, and epoxide hydrolase 1. Plasma SERPINA3 concentrations were significantly elevated in breast cancer patients 24 h post-DOX. Gene set enrichment analysis (GSEA) revealed upregulated pathways, including p53 signaling, apoptosis, and unfolded protein response. Integrated omics analysis revealed 2089 gene–protein pairs. GSEA of concordant gene–protein pairs implicated p53 signaling, apoptosis, and epithelial–mesenchymal transition in upregulated pathways, while oxidative phosphorylation and metabolic pathways were downregulated. Temporal comparison with a delayed timepoint (6 weeks post-DOX) uncovered dynamic remodeling of cardiac signaling, with early response dominated by inflammatory and apoptotic responses, and delayed response marked by cell cycle and DNA repair pathway activation. Conclusions: This integrated omics study reveals key molecular pathways and temporal changes in DOX-induced cardiotoxicity, identifying potential biomarkers for future cardioprotective strategies. Full article
(This article belongs to the Special Issue Advances in Cancer Treatment and Toxicity)
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17 pages, 2374 KB  
Article
Sex-Related Safety Signals of Sotorasib in Non-Small Cell Lung Cancer: A Real-World, Pharmacovigilance Study from the EudraVigilance Database
by Desirèe Speranza, Mariapia Marafioti, Martina Musarra, Vincenzo Cianci, Fausto Omero, Calogera Claudia Spagnolo, Marco Calabrò, Nicola Silvestris, Natasha Irrera and Mariacarmela Santarpia
Pharmaceuticals 2025, 18(10), 1574; https://doi.org/10.3390/ph18101574 - 19 Oct 2025
Viewed by 1102
Abstract
Background: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs). However, post-marketing pharmacovigilance is crucial to identify real-world safety signals including sex-specific differences that may [...] Read more.
Background: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs). However, post-marketing pharmacovigilance is crucial to identify real-world safety signals including sex-specific differences that may not be evident in controlled trial settings. Methods: This analysis reviewed 845 individual case safety reports (ICSRs) from the EudraVigilance (EV) database between 1 January 2021, and 8 April 2025, involving NSCLC patients treated with sotorasib. Adverse drug reactions (ADRs) were assessed by sex, seriousness, outcome, and system organ class (SOC). Disproportionality analyses were conducted to detect sex-specific safety signals, and results were compared with data from the CodeBreaK200 RCT by using a two-proportion z-test. Results: Among the ICSRs, 49.2% involved male and 40.1% female patients. Serious ADRs accounted for 47.5% of cases, with females at higher risk (relative risk [RR] = 1.31; 95% confidence interval (CI): 1.22–1.40; p < 0.0001). The most frequently reported SOCs were neoplasms (15.8%), gastrointestinal disorders (15.3%), and hepatobiliary disorders (11.5%). Four sex-specific safety signals were identified: women had a significantly increased risk of cholestasis (RR = 3.37) and hepatotoxicity (RR = 3.01), while men were less likely to report decreased appetite (RR = 0.20) and rash (RR = 0.14). Real-world data showed lower reporting of diarrhea, fatigue, nausea, and liver enzyme elevations (p < 0.0001). Conclusions: Real-world pharmacovigilance supports the RCT findings and highlights sex-specific risks, thus emphasizing the importance of sex-aware monitoring and personalized toxicity management. Full article
(This article belongs to the Special Issue Advances in Cancer Treatment and Toxicity)
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13 pages, 1501 KB  
Article
Predictive Value of Baseline Left Ventricular Global Longitudinal Strain for Cardiac Dysfunction in Patients with Moderate to High Risk of Cancer Therapy-Related Cardiovascular Toxicity
by Anna Borowiec, Patrycja Ozdowska, Magdalena Rosinska, Agnieszka Maria Zebrowska, Slawomir Jasek, Beata Kotowicz, Hanna Kosela-Paterczyk, Elzbieta Lampka, Zbigniew Nowecki and Jan Walewski
Pharmaceuticals 2025, 18(10), 1530; https://doi.org/10.3390/ph18101530 - 11 Oct 2025
Viewed by 1533
Abstract
Background: Anthracycline-based chemotherapy is associated with a risk of cancer therapy-related cardiac dysfunction (CTRCD), particularly in patients with moderate to high cardiovascular risk. Left ventricular global longitudinal strain (GLS) is a sensitive marker for early myocardial dysfunction, but the prognostic value of baseline [...] Read more.
Background: Anthracycline-based chemotherapy is associated with a risk of cancer therapy-related cardiac dysfunction (CTRCD), particularly in patients with moderate to high cardiovascular risk. Left ventricular global longitudinal strain (GLS) is a sensitive marker for early myocardial dysfunction, but the prognostic value of baseline GLS in this population remains unclear. Objective: We aimed to evaluate whether baseline GLS can predict CTRCD in moderate- to high-risk cancer patients undergoing anthracycline chemotherapy. Methods: In this prospective, single-center observational study, 80 anthracycline-naive cancer patients classified as moderate or high risk were enrolled. Baseline GLS was assessed via speckle-tracking echocardiography, with a threshold of ≥−18% considered decreased. Patients were followed for 12 months, and the primary endpoint was the development of CTRCD per ESC 2022 Cardio-oncology guidelines. Results: Of the 77 patients completing follow-up, 27.3% had decreased baseline GLS. CTRCD occurred in 62.4% of patients, with higher incidence among those with decreased GLS (76.7%) compared to those with normal GLS. In multivariable analysis, GLS ≥−18% was the only significant independent predictor of CTRCD (RR 12.0, 95% CI 2.0–71.9; p = 0.0065). All-cause mortality was also significantly higher in patients with decreased baseline GLS (19.1% vs. 1.8%, p = 0.018). Conclusions: Decreased baseline global longitudinal strain is an independent predictor of cancer therapy-related cardiac dysfunction and all-cause mortality in moderate- to high-risk patients receiving anthracycline therapy. These findings support the inclusion of baseline GLS in pre-treatment cardiovascular risk assessment, particularly in patients with an LVEF above 54%, to more effectively identify those who may benefit from early cardioprotective interventions. Full article
(This article belongs to the Special Issue Advances in Cancer Treatment and Toxicity)
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Review

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25 pages, 567 KB  
Review
From Genotype to Functional Risk: A Multi-Omic Approach to Predicting Thiopurine and Methotrexate Co-Therapy-Induced Liver Injury
by Dénes Molnár, Elizabeth Reznik and Pálma Porrogi
Pharmaceuticals 2026, 19(5), 733; https://doi.org/10.3390/ph19050733 - 6 May 2026
Viewed by 325
Abstract
The combination of thiopurine and methotrexate (MTX) is a standard co-therapy regimen for acute lymphoblastic leukemia (ALL). Despite its efficacy, this regimen is constrained by a narrow therapeutic window and considerable inter-individual variability, which heightens the risk of drug-induced liver injury (DILI). MTX-induced [...] Read more.
The combination of thiopurine and methotrexate (MTX) is a standard co-therapy regimen for acute lymphoblastic leukemia (ALL). Despite its efficacy, this regimen is constrained by a narrow therapeutic window and considerable inter-individual variability, which heightens the risk of drug-induced liver injury (DILI). MTX-induced metabolic strain further destabilizes cytokine-sensitive thiopurine detoxification pathways during systemic inflammation. Conventional pharmacogenetic (PGx) testing for TPMT and NUDT15 variants is effective in predicting myelosuppression, but often fails to detect hepatotoxicity as an adverse effect, suggesting a clinically significant genotype-phenotype difference. This review examines the molecular determinants of DILI, emphasizing the role of secondary metabolic pathways and transporter dynamics as key modulators of risk. The study describes cytokine-mediated (IL-6, TNF-α) transcriptional suppression of cytochrome P450 enzymes and hepatic transporters (SLCO1B1, ABCC2/4) not merely as secondary modulators, but as the primary determinants of localized, tissue-specific drug exposure through disrupted nuclear receptor signaling (PXR, CAR, HNF4α). This mechanism promotes functional phenoconversion and toxic molecular shunting, leading to increased intrahepatic drug exposure. It synthesizes the current knowledge on the metabolism of thiopurine and MTX, focusing on the genetic and non-genetic factors influencing toxicity and their interactions. The review also critically evaluates the limitations of static PGx-guided dosing. It highlights the need for comprehensive, real-time risk assessment that integrates gene-environment interactions, multi-omics data, and clinical monitoring to improve precision therapy for ALL. This approach combines extended PGx profiling, transcriptomic monitoring, and clinical biomarker assessment to provide a transformative strategy for precision drug delivery. Full article
(This article belongs to the Special Issue Advances in Cancer Treatment and Toxicity)
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25 pages, 6368 KB  
Review
The MDM2-p53 Axis in Osteosarcoma: Current Understanding of Regulatory Mechanisms and Targeted Therapeutic Strategies
by Wenxia Deng, Songyan Gao, Lige Yan, Qiuju Su and Si Chen
Pharmaceuticals 2026, 19(3), 476; https://doi.org/10.3390/ph19030476 - 13 Mar 2026
Viewed by 646
Abstract
Osteosarcoma, the most prevalent primary malignant bone tumor in children and adolescents, is characterized by high rates of metastasis, recurrence, and chemotherapy resistance, leading to suboptimal patient survival. The MDM2-p53 pathway plays a pivotal role in its tumorigenesis and progression, where dysregulation leads [...] Read more.
Osteosarcoma, the most prevalent primary malignant bone tumor in children and adolescents, is characterized by high rates of metastasis, recurrence, and chemotherapy resistance, leading to suboptimal patient survival. The MDM2-p53 pathway plays a pivotal role in its tumorigenesis and progression, where dysregulation leads to loss of p53 function. This review systematically elucidates the molecular mechanisms of this pathway and summarizes diverse targeted therapeutic strategies, including small-molecule MDM2 inhibitors, mutant p53 reactivators, and innovative modalities such as gene therapy and Proteolysis Targeting Chimeras (PROTACs). Despite demonstrating potent preclinical activity with low IC50 values, the clinical translation of these agents has faced significant challenges. Early-generation MDM2 inhibitors (e.g., RG7112, Idasanutlin) showed limited monotherapy efficacy and dose-limiting toxicities like thrombocytopenia, halting their development at early-phase clinical trials. In contrast, novel MDM2 inhibitors like APG-115 have advanced to Phase II trials, marking a significant breakthrough. Although not yet tested in dedicated osteosarcoma cohorts, their safety and efficacy in MDM2-amplified solid tumors provide a critical foundation for the development of precision medicine and combination regimens for osteosarcoma. Future efforts to accelerate drug development may leverage single-cell sequencing and AI-aided drug design to decipher osteosarcoma heterogeneity and optimize drug profiles for reduced toxicity. Full article
(This article belongs to the Special Issue Advances in Cancer Treatment and Toxicity)
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