Journal Article Epublish 3 citations
PubMed: 39940959 DOI: 10.3390/ijms26031191
Combinatorial Effects of Cisplatin and PARP Inhibitor Olaparib on Survival, Intestinal Integrity, and Microbiome Modulation in Murine Model.
Int J Mol Sci 26(3)
Authors: Mitsuki Matsumura, Hisako Fujihara, Kanna Maita, Moeko Miyakawa, Yushi Sakai, Ryoko Nakayama, Yumi Ito, Mitsuhiko Hasebe, Koji Kawaguchi, Yoshiki Hamada
Affiliations
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa, Japan.
- Department of Oral Hygiene, Tsurumi Junior College, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa, Japan.
- Department of Pathology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa, Japan.
- Department of Diagnostic Pathology, Tsurumi University Dental Hospital, Yokohama 230-8501, Kanagawa, Japan.
Abstract
This study investigated the effects of the poly (ADP-ribose) polymerase (PARP) inhibitor Olaparib, alone and in combination with cisplatin, on intestinal integrity, survival, and microbiome composition using a murine model. Statistical analyses were conducted using one-way analysis of variance with Bonferroni correction for multiple comparisons, considering -values of <0.05 as statistically significant. Microbiome profiling was performed using Qiime 2 software. Histopathological and microbiome analyses revealed Olaparib's protective effects on intestinal integrity, mitigating cisplatin-induced damage. The single administration of cisplatin caused significant histological damage, biochemical disruptions, and dysbiosis, characterized by an increase in pro-inflammatory microbiome, such as , and a decrease in beneficial short-chain fatty acid (SCFA)-producing microbiome. Conversely, the single administration of Olaparib was associated with an increase in SCFA-producing microbiome, such as , and exhibited minimal toxicity. The combination administration showed complicated outcomes, as follows: reduced cisplatin-induced cytotoxicity and increased SCFA-producing microbiome ratios, yet the long-term effects revealed reduced survival rates in the cisplatin group and sustained weight gain suppression. These findings emphasize Olaparib's potential in enhancing intestinal barrier integrity, reducing inflammation, and positively modulating microbiome diversity. However, the entangled pharmacodynamic interactions in the combination administration underscore the need for further investigation. The study highlights the potential of microbiome-targeted interventions in improving therapeutic outcomes for both cancer treatment and inflammatory bowel disease management.
MeSH
Dysbiosis, Poly(Adp-Ribose) Polymerase Inhibitors, Poly(Adp-Ribose) Polymerases, Poly Adenosine Diphosphate Ribose, Pyroptosis, Therapeutics