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Cytotoxicity on Pharmaceutical Interactions in Chemotherapy
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Cytotoxicity on Pharmaceutical Interactions in Chemotherapy

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

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 8326

Special Issue Editor

Prof. Dr. Yoshihiro Uesawa

E-Mail Website
Guest Editor
Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo 204-858, Japan
Interests: computational toxicology; pharmacokinetics; pharmacovigilance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A wide variety of anticancer drugs are used for chemotherapy depending on the type of cancer. Many of these anticancer agents have cytotoxic effects on tumor cells as a major mechanism for their anticancer effects. However, insufficient tumor cell selectivity may result in a risk of comorbid side effects, including hematotoxicity due to myelosuppression. Because chemotherapy is often achieved using a combination of drugs, the relationship between these antitumor effects and side effects and anticancer drugs is complex.

The purpose of this Special Issue is to integrate knowledge, including mechanisms of clinically and biochemically useful expression of pharmacological interactions. In other words, it is expected that findings relevant to this topic will be based on the results of biochemical studies through in vivo and in vitro experiments and data accumulated in a variety of clinical studies, including database studies. This combined knowledge allows molecular interpretations of chemotherapy and may contribute to improved clinical outcomes of anticancer therapy.

Prof. Dr. Yoshihiro Uesawa
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • tumor specificity
  • PK/PD interaction
  • adverse effect
  • anticancer drug
  • cytotoxicity
  • chemotherapy
  • cell signaling
  • molecular mechanisms
  • translational research

Published Papers (4 papers)

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Research

10 pages, 909 KiB  
Article
Nuclear Receptor and Stress Response Pathways Associated with Antineoplastic Agent-Induced Diarrhea
by Mashiro Okunaka, Daisuke Kano and Yoshihiro Uesawa
Int. J. Mol. Sci. 2022, 23(20), 12407; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012407 - 17 Oct 2022
Cited by 3 | Viewed by 1485
Abstract
In severe cases, antineoplastic agent-induced diarrhea may be life-threatening; therefore, it is necessary to determine the mechanism of toxicity and identify the optimal management. The mechanism of antineoplastic agent-induced diarrhea is still unclear but is often considered to be multifactorial. The aim of [...] Read more.
In severe cases, antineoplastic agent-induced diarrhea may be life-threatening; therefore, it is necessary to determine the mechanism of toxicity and identify the optimal management. The mechanism of antineoplastic agent-induced diarrhea is still unclear but is often considered to be multifactorial. The aim of this study was to determine the molecular initiating event (MIE), which is the initial interaction between molecules and biomolecules or biosystems, and to evaluate the MIE specific to antineoplastic agents that induce diarrhea. We detected diarrhea-inducing drug signals based on adjusted odds ratios using the Food and Drug Administration Adverse Event Reporting System. We then used the quantitative structure-activity relationship platform of Toxicity Predictor to identify potential MIEs that are specific to diarrhea-inducing antineoplastic agents. We found that progesterone receptor antagonists were potential MIEs associated with diarrhea. The findings of this study may help improve the prediction and management of antineoplastic agent-induced diarrhea. Full article
(This article belongs to the Special Issue Cytotoxicity on Pharmaceutical Interactions in Chemotherapy)
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25 pages, 4720 KiB  
Article
Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo
by Oksana V. Salomatina, Aleksandra V. Sen’kova, Arseny D. Moralev, Innokenty A. Savin, Nina I. Komarova, Nariman F. Salakhutdinov, Marina A. Zenkova and Andrey V. Markov
Int. J. Mol. Sci. 2022, 23(11), 6214; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116214 - 01 Jun 2022
Cited by 4 | Viewed by 2019
Abstract
It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides [...] Read more.
It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates. Full article
(This article belongs to the Special Issue Cytotoxicity on Pharmaceutical Interactions in Chemotherapy)
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13 pages, 3760 KiB  
Article
Tumor-Specificity, Neurotoxicity, and Possible Involvement of the Nuclear Receptor Response Pathway of 4,6,8-Trimethyl Azulene Amide Derivatives
by Kotone Naitoh, Yuta Orihara, Hiroshi Sakagami, Takumi Miura, Keitaro Satoh, Shigeru Amano, Kenjiro Bandow, Yosuke Iijima, Kota Kurosaki, Yoshihiro Uesawa, Masashi Hashimoto and Hidetsugu Wakabayashi
Int. J. Mol. Sci. 2022, 23(5), 2601; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052601 - 26 Feb 2022
Cited by 3 | Viewed by 1872
Abstract
Background: Very few papers covering the anticancer activity of azulenes have been reported, as compared with those of antibacterial and anti-inflammatory activity. This led us to investigate the antitumor potential of fifteen 4,6,8-trimethyl azulene amide derivatives against oral malignant cells. Methods: 4,6,8-Trimethyl azulene [...] Read more.
Background: Very few papers covering the anticancer activity of azulenes have been reported, as compared with those of antibacterial and anti-inflammatory activity. This led us to investigate the antitumor potential of fifteen 4,6,8-trimethyl azulene amide derivatives against oral malignant cells. Methods: 4,6,8-Trimethyl azulene amide derivatives were newly synthesized. Anticancer activity was evaluated by tumor-specificity against four human oral squamous cell carcinoma (OSCC) cell lines over three normal oral cells. Neurotoxicity was evaluated by cytotoxicity against three neuronal cell lines over normal oral cells. Apoptosis induction was evaluated by Western blot and cell cycle analyses. Results: Among fifteen derivatives, compounds 7, 9, and 15 showed the highest anticancer activity, and relatively lower neurotoxicity than doxorubicin, 5-fluorouracil (5-FU), and melphalan. They induced the accumulation of a comparable amount of a subG1 population, but slightly lower extent of caspase activation, as compared with actinomycin D, used as an apoptosis inducer. The quantitative structure–activity relationship analysis suggests the significant correlation of tumor-specificity with a 3D shape of molecules, and possible involvement of inflammation and hormone receptor response pathways. Conclusions: Compounds 7 and 15 can be potential candidates of a lead compound for developing novel anticancer drugs. Full article
(This article belongs to the Special Issue Cytotoxicity on Pharmaceutical Interactions in Chemotherapy)
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21 pages, 2837 KiB  
Article
Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment
by Fabio Ntagwabira, Madison Trujillo, Taylor McElroy, Taurean Brown, Pilar Simmons, Delawerence Sykes and Antiño R. Allen
Int. J. Mol. Sci. 2022, 23(4), 2008; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042008 - 11 Feb 2022
Cited by 6 | Viewed by 2149
Abstract
Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient’s quality of life. Additional therapies are needed to [...] Read more.
Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient’s quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity. Full article
(This article belongs to the Special Issue Cytotoxicity on Pharmaceutical Interactions in Chemotherapy)
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