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Background and Purpose: Opioids are commonly used for the management of cancer‐associated pain and chemotherapy‐induced diarrhoea. The chemotherapeutic irinotecan (CPT‐11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN‐38 glucuronide (SN‐38G) by bacterial β‐glucuronidases to the active 7‐ethyl‐10‐hydroxycamptothecin (SN‐38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT‐11 anti‐tumour efficacy and GI toxicity are exacerbated by opioid co‐administration. Experimental Approach: Eight‐week‐old C57BL/6 male mice were co‐administration with CPT‐11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC–MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT‐11. Histological analysis and quantitative real‐time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT‐11 metabolism. Key Results: Gut microbiome analysis showed that morphine treatment induced enrichment of β‐glucuronidase‐producing bacteria in the intestines of CPT‐11‐treated mice, resulting in SN‐38 accumulation and exacerbation of GI toxicity in the small intestine. Oral administration of both antibiotics and glucuronidase inhibitor protected mice against GI toxicity induced with CPT‐11 and morphine co‐administration, implicating a microbiome‐dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN‐38 and compromised CPT‐11 anti‐tumour efficacy, this seemed to be microbiome independent. Conclusion and Implications: Gut microbiota play a significant role in opioid and chemotherapeutic agent drug–drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT‐11 in patients on opioids. [ABSTRACT FROM AUTHOR]

Background and Purpose: Proteasome inhibitors represent a novel class of anti-tumour agents that have clinical efficacy against haematological and solid cancers. The anti-apoptotic protein BAG3 is a member of the Bcl-2-associated athanogene family. We have previously shown that BAG3 is up-regulated after exposure to proteasome inhibitors and that inhibition of BAG3 sensitized cells to apoptosis induced by proteasome inhibition. However, the mechanisms by which proteasome inhibition induced BAG3 expression remained unclear and the present experiments were designed to elucidate these mechanisms.Experimental Approach: Effects of the proteasome inhibitor MG132 on activation of mitogenic signalling pathways were evaluated in kidney cancer cells (A498, Caki1, Caki2), with Western blotting. Specific inhibitors against individual mitogenic signalling pathways, real-time reverse transcription-polymerase chain reaction and luciferase reporter assays were used to investigate the roles of mitogenic signalling pathways in BAG3 induction after proteasome inhibition. Cell death was evaluated using Annexin V/propidium iodide staining and subsequent FACS.Key Results: MG132 activated several key mitogenic signalling pathways including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activities. Induction of BAG3 by MG132 was inhibited by blocking JNK, but not ERK1/2 and p38 MAPK signalling pathways. In addition, SP600125 and dominant-negative JNK1 suppressed BAG3 promoter-driven reporter gene expression. Furthermore, activation of the JNK pathway induced BAG in kidney cancer cells after treatment with MG132.Conclusions and Implications: Our results suggested that the JNK pathway was associated with the protective response against proteasome inhibition, by mediating induction of BAG3. [ABSTRACT FROM AUTHOR]