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Pharmaceuticals
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Cancer Drugs Treatment and Toxicity
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Cancer Drugs Treatment and Toxicity

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 27216

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, 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, the majority of 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 is suggested that increased oxidative stress, inflammation, mitochondrial dysfunction, and cell death are prominent mechanisms involved in the development and progression of these diseases. Recent data suggest that researchers are investigating various therapeutic approaches, such as miRNA technology, anti-oxidative and anti-inflammatory drugs, anti-apoptotic therapeutic options, cell therapy, and exosomes.

The journal 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 muscle. These articles can be of a wider scope on 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 will also welcome any current therapeutic strategies being investigated to attenuate anticancer-drug-induced side effects in the tissues.

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 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. 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

Published Papers (8 papers)

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Research

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12 pages, 1700 KiB  
Article
Comprehensive Analysis of Chemotherapeutic Agents That Induce Infectious Neutropenia
by Mashiro Okunaka, Daisuke Kano, Reiko Matsui, Toshikatsu Kawasaki and Yoshihiro Uesawa
Pharmaceuticals 2021, 14(7), 681; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070681 - 15 Jul 2021
Cited by 15 | Viewed by 2807
Abstract
Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of [...] Read more.
Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of clinical trials have currently highlighted the risk of CIN with each chemotherapy regimen, only a few ones have comprehensively examined the risk associated with all chemotherapeutic agents. Therefore, this study aimed to investigate the risk factors and characteristics of CIN caused by each neoplastic agent using data from the large voluntary reporting Food and Drug Administration Adverse Event Reporting System database. Initially, univariate analysis showed that an age ≥ 65 years, the female sex, and treatment with chemotherapeutic agents were factors that caused CIN. Then, cluster and component analyses showed that cytotoxic agents (i.e., alkylating agents, antimetabolic agents, antineoplastic antibiotics, platinating agents, and plant-derived alkaloids) were associated with infection following neutropenia. This comprehensive analysis comparing CIN risk suggests that elderly or underweight patients treated with cytotoxic drugs require particularly careful monitoring. Full article
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
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20 pages, 3747 KiB  
Article
Metronomic 5-Fluorouracil Delivery Primes Skeletal Muscle for Myopathy but Does Not Cause Cachexia
by Dean G. Campelj, Cara A. Timpani, Tabitha Cree, Aaron C. Petersen, Alan Hayes, Craig A. Goodman and Emma Rybalka
Pharmaceuticals 2021, 14(5), 478; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050478 - 17 May 2021
Cited by 6 | Viewed by 3484
Abstract
Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective [...] Read more.
Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective against the chemotoxic challenge exerted by 5FU. Additionally, we explore the molecular signature of 5FU treatment. Male Balb/c mice received metronomic tri-weekly intraperitoneal delivery of 5FU (23 mg/kg), with and without BGP-15 (15 mg/kg), 6 times in total over a 15 day treatment period. We demonstrated that neither 5FU, nor 5FU combined with BGP-15, affected body composition indices, skeletal muscle mass or function. Adjuvant BGP-15 treatment did, however, prevent the 5FU-induced phosphorylation of p38 MAPK and p65 NF-B subunit, signalling pathways involved in cell stress and inflammatory signalling, respectively. This as associated with mitoprotection. 5FU reduced the expression of the key cytoskeletal proteins, desmin and dystrophin, which was not prevented by BGP-15. Combined, these data show that metronomic delivery of 5FU does not elicit physiological consequences to skeletal muscle mass and function but is implicit in priming skeletal muscle with a molecular signature for myopathy. BGP-15 has modest protective efficacy against the molecular changes induced by 5FU. Full article
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
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12 pages, 2321 KiB  
Article
Evaluation of the Expression Profile of Irinotecan-Induced Diarrhea in Patients with Colorectal Cancer
by Mashiro Okunaka, Daisuke Kano, Reiko Matsui, Toshikatsu Kawasaki and Yoshihiro Uesawa
Pharmaceuticals 2021, 14(4), 377; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040377 - 19 Apr 2021
Cited by 8 | Viewed by 2516
Abstract
Irinotecan (CPT-11) is widely used for the treatment of unresectable colorectal cancer in combination with fluoropyrimidines, such as 5-fluorouracil and S-1. Diarrhea is one of the adverse effects associated with CPT-11 and frequently reported by patients treated with CPT-11-containing regimens combined with oral [...] Read more.
Irinotecan (CPT-11) is widely used for the treatment of unresectable colorectal cancer in combination with fluoropyrimidines, such as 5-fluorouracil and S-1. Diarrhea is one of the adverse effects associated with CPT-11 and frequently reported by patients treated with CPT-11-containing regimens combined with oral fluoropyrimidines. However, the mechanisms involved in this process, as well as whether fluctuations in the frequency and differences in the onset time of diarrhea with each CPT-11-containing regimen are caused by drug interactions remain unclear. Therefore, we examined the incidence of diarrhea caused by each CPT-11-containing regimen in patients with colorectal cancer using data from the large voluntary reporting Japanese Adverse Drug Event Report (JADER) database. Firstly, we searched for suspected drugs related to the occurrence of diarrhea using reported odds ratio and calculated the signal score to assess drug–drug interactions. Subsequently, we conducted a time-to-onset analysis using Weibull distribution. The results showed that the combination of CPT-11 with S-1 increased the frequency of diarrhea due to a pharmacological interaction but delayed its onset. The present results may contribute to the appropriate management of drug-induced adverse effects by healthcare professionals. Full article
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
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20 pages, 8876 KiB  
Article
Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis
by Fatima Bianca A. Dessouki, Rakesh C. Kukreja and Dinender K. Singla
Pharmaceuticals 2020, 13(12), 450; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120450 - 09 Dec 2020
Cited by 18 | Viewed by 3458
Abstract
Doxorubicin (Dox)-induced muscle toxicity (DIMT) is a common occurrence in cancer patients; however, the cause of its development and progression is not established. We tested whether inflammation-triggered cell death, “pyroptosis” plays a role in DIMT. We also examined the potential role of exosomes [...] Read more.
Doxorubicin (Dox)-induced muscle toxicity (DIMT) is a common occurrence in cancer patients; however, the cause of its development and progression is not established. We tested whether inflammation-triggered cell death, “pyroptosis” plays a role in DIMT. We also examined the potential role of exosomes derived from embryonic stem cells (ES-Exos) in attenuating DIMT. C57BL/6J mice (10 ± 2 wks age) underwent the following treatments: Control (saline), Dox, Dox+ES-Exos, and Dox+MEF-Exos (mouse-embryonic fibroblast-derived exosomes, negative control). Our results demonstrated that Dox significantly reduced muscle function in mice, which was associated with a significant increase in NLRP3 inflammasome and initiation marker TLR4 as compared with controls. Pyroptosis activator, ASC, was significantly increased compared to controls with an upregulation of specific markers (caspase-1, IL-1β, and IL-18). Treatment with ES-Exos but not MEF-Exos showed a significant reduction in inflammasome and pyroptosis along with improved muscle function. Additionally, we detected a significant increase in pro-inflammatory cytokines (TNF-α and IL-6) and inflammatory M1 macrophages in Dox-treated animals. Treatment with ES-Exos decreased M1 macrophages and upregulated anti-inflammatory M2 macrophages. Furthermore, ES-Exos showed a significant reduction in muscular atrophy and fibrosis. In conclusion, these results suggest that DIMT is mediated through inflammation and pyroptosis, which is attenuated following treatment with ES-Exos. Full article
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
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14 pages, 32018 KiB  
Article
The Alpha-Lipoic Acid Improves Survival and Prevents Irinotecan-Induced Inflammation and Intestinal Dysmotility in Mice
by Daniely V. S. Costa, Deiziane V. S. Costa, Caren N. S. Sousa, Angeline M. H. P. Silva, Ingridy S. Medeiros, Dainesy S. Martins, Conceição S. Martins, Ana L. V. Pequeno, Roberto C. P. Lima-Júnior, Pedro M. G. Soares, Silvânia M. M. Vasconcelos, Gerly A. C. Brito and Emmanuel P. Souza
Pharmaceuticals 2020, 13(11), 361; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110361 - 03 Nov 2020
Cited by 7 | Viewed by 2484
Abstract
Irinotecan, an anticancer drug, induces diarrhea and intestinal inflammation, resulting in an increase in the cost of care and in treatment delays. In this study, we investigated whether alpha-lipoic acid (α-LA) could improve irinotecan-mediated intestinal inflammation, diarrhea and dysmotility. Intestinal mucositis was induced [...] Read more.
Irinotecan, an anticancer drug, induces diarrhea and intestinal inflammation, resulting in an increase in the cost of care and in treatment delays. In this study, we investigated whether alpha-lipoic acid (α-LA) could improve irinotecan-mediated intestinal inflammation, diarrhea and dysmotility. Intestinal mucositis was induced by irinotecan injection (75 mg/kg, i.p., for 4 days) in Swiss mice. α-LA (50, 100 or 200 mg/kg, gavage) was administered daily 1 h before the injection of irinotecan. Duodenum tissues were obtained for inflammation and proliferation analysis. The outcomes: diarrhea, intestinal dysmotility, weight body loss and survival were evaluated. Compared with the control condition, irinotecan diminished (p < 0.05) intestinal villus height, caused a loss of crypt integrity and intense inflammatory cell infiltration, increased myeloperoxidase (MPO), IL-6 and IL-1β levels and decreased reduced glutathione (GSH) levels in duodenum segments and increased gastric retention and decreased liquid retention in the medial intestinal segment, resulting in increased intestinal transit, severe diarrhea and reduced survival (approximately 72%). Furthermore, α-LA (200 mg/kg) pretreatment ameliorated (p < 0.05) these irinotecan-induced effects. Our findings show that α-LA reduced irinotecan-induced inflammation, intestinal dysmotility and diarrhea, resulting in improved survival. α-LA may be a useful therapeutic agent for the treatment of gut dysmotility in patients with intestinal mucositis associated with irinotecan treatment. Full article
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
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17 pages, 16062 KiB  
Article
Pirfenidone and Vitamin D Ameliorate Cardiac Fibrosis Induced by Doxorubicin in Ehrlich Ascites Carcinoma Bearing Mice: Modulation of Monocyte Chemoattractant Protein-1 and Jun N-terminal Kinase-1 Pathways
by Mohamed A. Saleh, Samar A. Antar, Reem M. Hazem and Mona F. El-Azab
Pharmaceuticals 2020, 13(11), 348; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110348 - 28 Oct 2020
Cited by 19 | Viewed by 3096
Abstract
Treatment of breast cancer with doxorubicin causes numerous side effects, of which cardiac fibrosis is considered the main one. This study was designed to investigate the underlying molecular mechanisms for the potential anti-fibrotic effect of pirfenidone and vitamin D against doxorubicin-induced cardiac fibrosis. [...] Read more.
Treatment of breast cancer with doxorubicin causes numerous side effects, of which cardiac fibrosis is considered the main one. This study was designed to investigate the underlying molecular mechanisms for the potential anti-fibrotic effect of pirfenidone and vitamin D against doxorubicin-induced cardiac fibrosis. Seventy mice carrying solid Ehrlich’s ascites carcinoma (EAC) discs on the ventral side were treated with orally administered pirfenidone (500 mg/kg) and intraperitoneal injection of vitamin D (0.5 µg/kg) either individually or in combination with a doxorubicin (15 mg/kg; i.p.) single dose. All treatments commenced one week post-tumor inoculation and continued for 14 days. Compared to control EAC mice, the doxorubicin group showed a significant increase in heart and left ventricle weights, troponin T, and creatinine kinase serum levels. Furthermore, the doxorubicin group depicts a high expression of monocyte chemoattractant protein (MCP-1), nuclear factor-kappa B (NF-κB), transforming growth factor-beta 1 (TGF-β1), smad3, Jun N-terminal Kinase-1 (JNK1), and alpha-smooth muscle actin (α-SMA). Treatment with pirfenidone or vitamin D significantly decreased all of these parameters. Furthermore, the expression of smad7 was downregulated by doxorubicin and improved by pirfenidone or vitamin D. Furthermore, all treated groups showed a marked decrease in tumor weight and volume. Current data demonstrate that pirfenidone and vitamin D represent an attractive approach to ameliorate the cardiac fibrosis produced by doxorubicin through inhibiting both JNK1 signaling and MCP-1 inflammatory pathways, thus preserving heart function. Further, this combination demonstrated an anti-tumor effect to combat breast cancer. Full article
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
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19 pages, 1025 KiB  
Article
Cardiotoxicity Associated with Gemcitabine: Literature Review and a Pharmacovigilance Study
by Marc Hilmi, Stéphane Ederhy, Xavier Waintraub, Christian Funck-Brentano, Ariel Cohen, Aurore Vozy, Bénédicte Lebrun-Vignes, Javid Moslehi, Lee S. Nguyen and Joe-Elie Salem
Pharmaceuticals 2020, 13(10), 325; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100325 - 21 Oct 2020
Cited by 21 | Viewed by 3584
Abstract
Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in [...] Read more.
Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May 2019. Then, we used VigiBase, the World Health Organization’s global database of individual case safety reports, to compare CV-ADR reporting associated with gemcitabine against the full database between inception and 1 April 2019. We used the information component (IC), an indicator value for disproportionate Bayesian reporting. A positive lower end of the 95% credibility interval for the IC (IC025) ≥ 0, is deemed significant. Results: In VigiBase, 46,898 reports were associated with gemcitabine on a total of 18,908,940 in the full database. Gemcitabine was associated with higher reporting for myocardial ischemia (MI, n: 119), pericardial diseases (n: 164), supraventricular arrhythmias (SVA, n: 308) and heart failure (HF, n: 484) versus full database with IC025 ranging between 0.40 and 2.81. CV-ADR were associated with cardiovascular death in up to 17% of cases. Conclusion: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design. Full article
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
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23 pages, 2072 KiB  
Review
Anticancer Drug-Induced Cardiotoxicity: Insights and Pharmacogenetics
by Archana Adhikari, Syed Mohammed Basheeruddin Asdaq, Maitham A. Al Hawaj, Manodeep Chakraborty, Gayatri Thapa, Nihar Ranjan Bhuyan, Mohd. Imran, Mohammed Kanan Alshammari, Mohammed M. Alshehri, Aishah Ali Harshan, Abeer Alanazi, Bushra Dhuhayyan Alhazmi and Nagaraja Sreeharsha
Pharmaceuticals 2021, 14(10), 970; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14100970 - 25 Sep 2021
Cited by 17 | Viewed by 4270
Abstract
The advancement in therapy has provided a dramatic improvement in the rate of recovery among cancer patients. However, this improved survival is also associated with enhanced risks for cardiovascular manifestations, including hypertension, arrhythmias, and heart failure. The cardiotoxicity induced by chemotherapy is a [...] Read more.
The advancement in therapy has provided a dramatic improvement in the rate of recovery among cancer patients. However, this improved survival is also associated with enhanced risks for cardiovascular manifestations, including hypertension, arrhythmias, and heart failure. The cardiotoxicity induced by chemotherapy is a life-threatening consequence that restricts the use of several chemotherapy drugs in clinical practice. This article addresses the prevalence of cardiotoxicity mediated by commonly used chemotherapeutic and immunotherapeutic agents. The role of susceptible genes and radiation therapy in the occurrence of cardiotoxicity is also reviewed. This review also emphasizes the protective role of antioxidants and future perspectives in anticancer drug-induced cardiotoxicities. Full article
(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)
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