SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4

Wong, Deysi Viviana Tenazoa; Ribeiro-Filho, Helder Veras; Wanderley, Carlos W.; Leite, Caio A.; Lima, Jonilson Berlink; Assef, Alexia Nathália Brígido; Cajado, Aurilene Gomes; Batista, Gabriela Loiola Ponte; González, Rafael Holanda; Silva, Karla Oliveira; Borges, Luis Philipi Carvalho; Alencar, Nylane Maria Nunes de; Wilke, Diego Veras; Cunha, Thiago Mattar; Figueira, Ana Carolina Migliorini; Cunha, Fernando Q.; Lima-Júnior, Roberto César Pereira

doi:10.1007/s00280-019-03844-z

Cited by 16 publications

(11 citation statements)

References 49 publications

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“…For instance, TLR2‐ and TLR9‐dependent cell signalling has been implicated in mucositis pathogenesis by orchestrating deleterious inflammatory mechanisms (Wong et al, 2015). Additionally, SN‐38, the active irinotecan metabolite, has been suggested to selectively antagonize LPS agonistic function on TLR4 by inhibiting the LPS‐driven acute inflammatory response (Wong et al, 2019). Interestingly, the TLR4 was shown to play essential regulatory functions in a broad spectrum of biological processes, such as cytokine and chemokine production, regulation of inflammatory responses, which may affect chemotherapy‐induced diarrhoea.…”

Section: Discussionmentioning

confidence: 99%

“…Among the TLRs family members, TLR2 and TLR9 have been implicated in the pathogenesis of irinotecan‐induced intestinal mucositis and diarrhoea (Wong et al, 2015). Irinotecan was also found to antagonize lipopolysaccharide (LPS)‐driven acute inflammatory responses by targeting TLR4 (Wong et al, 2019). Intriguingly, previous studies have reported a harmful role of TLR4 in irinotecan‐related mucositis in mice (Khan et al, 2018; Wardill, Bowen, et al, 2016; Wardill, Gibson, et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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TLR4 deficiency upregulates TLR9 expression and enhances irinotecan‐related intestinal mucositis and late‐onset diarrhoea

Wong

Holanda

Cajado

et al. 2021

British J Pharmacology

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Background and purpose Severe diarrhoea, a common gastrointestinal manifestation of anticancer treatment with irinotecan, might involve single nucleotide polymorphisms (SNPs) of toll‐like receptors (TLRs), described as critical bacterial sensors in the gut. Here, colorectal cancer patients carrying missense TLR4 A896G (rs4986790) or C1,196T (rs4986791) SNPs and Tlr4 knockout (Tlr4−/−) mice were given irinotecan to investigate the severity of the induced diarrhoea. Experimental approach Forty‐six patients treated with irinotecan‐based regimens had diarrhoea severity analysed according to TLR4 genotypes. In the experimental setting, wild‐type (WT) or Tlr4−/− mice were given irinotecan (45 or 75 mg·kg−1, i.p.) or saline (3 ml·kg−1). Diarrhoea severity was evaluated by measuring intestinal injury and inflammatory markers expression after animals were killed. Key results All patients with TLR4 SNPs chemotherapy‐treated presented diarrhoea, whereas gastrointestinal toxicity was observed in 50% of the wild homozygous individuals. Mice injected with irinotecan presented systemic bacterial translocation and increased TLR4 immunostaining in the intestine. In line with the clinical findings, Tlr4 gene deficiency enhanced irinotecan‐related diarrhoea and TLR9 expression in mice. An increased myeloperoxidase activity and Il‐18 expression along with IL‐10 decreased production in Tlr4−/− mice also indicated an intensified intestinal damage and inflammatory response. Conclusion and implications TLR4 deficiency upregulates TLR9 expression and enhances intestinal damage and the severity of late‐onset diarrhoea during irinotecan‐based treatment. Identifying patients genetically predisposed to chemotherapy‐associated diarrhoea is a strategy toward precision medicine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TLR4 deficiency upregulates TLR9 expression and enhances irinotecan‐related intestinal mucositis and late‐onset diarrhoea

Wong

Holanda

Cajado

et al. 2021

British J Pharmacology

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“…SN-38 has been demonstrated to inhibit acute inflammatory response by blocking LPS-driven toll-like receptor 4 signaling in macrophages. 55 It has also been shown that topoisomerase-1 inhibitors can inhibit the inflammatory genes and protect animals from LPS-induced death by regulating RNA polymerase II activity. 56 Hence, it is plausible that low-dose SN-38 may play a dual role in immunomodulation by robustly activating the antitumor immune response and curbing acute inflammatory response, which may cause unwanted side effects.…”

Section: Discussionmentioning

confidence: 99%

Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3

Chung

Khan

Wang

et al. 2021

J Immunother Cancer

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BackgroundStimulating antitumor immunity by blocking programmed death-1 (PD-1) or its ligand (programmed death-ligand 1 (PD-L1) is a promising antitumor therapy. However, numerous patients respond poorly to PD-1/PD-L1 blockade. Unresponsiveness to immune-checkpoint blockade (ICB) can cast significant challenges to the therapeutic options for patients with hard-to-treat tumors. There is an unmet clinical need to establish new therapeutic approaches for mitigating ICB unresponsiveness in patients. In this study, we investigated the efficacy and role of low-dose antineoplastic agent SN-38 or metformin in sensitizing unresponsive tumors to respond to ICB therapy.MethodsWe assessed the significant pathological relationships between PD-L1 and FOXO3 expression and between PD-L1 and c-Myc or STAT3 expression in patients with various tumors. We determined the efficacy of low-dose SN-38 or metformin in sensitizing unresponsive tumors to respond to anti-PD-1 therapy in a syngeneic tumor system. We deciphered novel therapeutic mechanisms underlying the SN-38 and anti-PD-1 therapy-mediated engagement of natural killer (NK) or CD8+ T cells to infiltrate tumors and boost antitumor immunity.ResultsWe showed that PD-L1 protein level was inversely associated with FOXO3 protein level in patients with ovarian, breast, and hepatocellular tumors. Low-dose SN-38 or metformin abrogated PD-L1 protein expression, promoted FOXO3 protein level, and significantly increased the animal survival rate in syngeneic mouse tumor models. SN-38 or metformin sensitized unresponsive tumors responding to anti-PD-1 therapy by engaging NK or CD8+ T cells to infiltrate the tumor microenvironment (TME) and secret interferon-γ and granzyme B to kill tumors. SN-38 suppressed the levels of c-Myc and STAT3 proteins, which controlled PD-L1 expression. FOXO3 was essential for SN38-mediated PD-L1 suppression. The expression of PD-L1 was compellingly linked to that of c-Myc or STAT3 in patients with the indicated tumors.ConclusionWe show that SN-38 or metformin can boost antitumor immunity in the TME by inhibiting c-Myc and STAT3 through FOXO3 activation. These results may provide novel insight into ameliorating patient response to overarching immunotherapy for tumors.

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“…Finally, topoisomerase I inhibitors are also used. This is the case of SN-38, the active metabolite of irinotecan (CPT-11), a camptothecin analog, that exerts a cytotoxic effect by inhibiting DNA topoisomerase I [ 60 ]. SN-38 is very potent, showing around 1000-fold potency than CPT-11.…”

Section: Adcs In Gynecological Tumors: Structure and Functionmentioning

confidence: 99%

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

2021

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In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors.

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SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4

Cited by 16 publications

References 49 publications

TLR4 deficiency upregulates TLR9 expression and enhances irinotecan‐related intestinal mucositis and late‐onset diarrhoea

TLR4 deficiency upregulates TLR9 expression and enhances irinotecan‐related intestinal mucositis and late‐onset diarrhoea

Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

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