Mechanisms of topoisomerase I inhibition by anticancer drugs

Pommier, ﻿Yves; Barceló, Juana; Furuta, Takahisa; Takemura, Haruyuki; Sordet, Olivier

doi:10.1007/978-1-4615-0141-1_2

Cited by 12 publications

(12 citation statements)

References 167 publications

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“…Irinotecan, a topoisomerase 1 inhibitor, is a chemotherapeutic agent widely used for the treatment of a variety of cancers, including small cell lung cancer, gastrointestinal cancer, and breast cancer [ 8 – 11 ]. However, the role of irinotecan in the tumor–immunity cycle has not yet been investigated and there are few clinical studies evaluating the combination of irinotecan with PD-L1/PD-1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies

Iwai¹,

Sugimoto²,

Wakita³

et al. 2018

Oncotarget

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Anti-PD-L1 antibodies inhibit interactions between PD-L1 and PD-1 and interactions between PD-L1 and B7-1, thereby reinvigorating anticancer immunity. Although there are numerous ongoing clinical studies evaluating combinations of standard chemotherapies and anti-PD-L1 antibodies, irinotecan has not yet been investigated in this context so there is little information about its compatibility with anti-PD-L1 antibodies. Here we investigated the efficacy of anti-PD-L1 antibody in combination with irinotecan and the role of irinotecan in the tumor–immunity cycle in an FM3A murine tumor model. Despite a transient decrease in lymphocytes in the peripheral blood after irinotecan treatment, the antitumor activity of anti-PD-L1 antibody plus irinotecan was significantly greater than each agent alone. Irinotecan in combination with anti-PD-L1 antibody enhanced proliferation of CD8+ cells in both tumors and lymph nodes, and the number of tumor-infiltrating CD8+ cells was higher than either irinotecan or anti-PD-L1 antibody monotherapy. Irinotecan was found to decrease the number of Tregs in lymph nodes and tumors, and specific depletion of Tregs by anti-folate receptor 4 antibodies was found to enhance the proliferation of CD8+ cells in this model. In addition, irinotecan augmented MHC class I expression on tumor cells and concurrently increased PD-L1 expression on tumor cells and tumor-infiltrating immune cells. These results indicate that irinotecan may enhance the effect of T cell activation caused by anti-PD-L1 treatment by reducing Tregs and augmenting MHC class I–mediated tumor antigen presentation, and concurrent upregulation of PD-L1 expression can be blocked by the anti-PD-L1 antibody. These interactions may contribute to the superior combination effect.

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Section: Introductionmentioning

confidence: 99%

Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies

Iwai¹,

Sugimoto²,

Wakita³

et al. 2018

Oncotarget

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“…Camptothecin and its analog topotecan (TPT) are important anticancer agents for the treatment of various human malignancies in the clinic [6–8]. The major mechanism of action of camptothecin and TPT (Figure 1) is due to the stabilization of transient complexes formed between topo I and DNA (cleavable complexes), resulting in the formation of highly toxic double-strand breaks in tumor cells, causing cell death [2, 3, 5]. While other mechanisms of actions of TPT that are independent of topo I have also been suggested, including induction of oxidative stress [9, 10] and inhibition of hypoxia-inducible factor [11, 12], there is very little known about how TPT induces oxidative stress in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Synergistic enhancement of topotecan-induced cell death by ascorbic acid in human breast MCF-7 tumor cells

Sinha

Erve

Kumar

et al. 2017

Free Radical Biology and Medicine

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Topotecan, a derivative of camptothecin, is an important anticancer drug for the treatment of various human cancers in the clinic. While the principal mechanism of tumor cell killing by topotecan is due to its interactions with topoisomerase I, other mechanisms, e.g., oxidative stress induced by reactive free radicals, have also been proposed. However, very little is known about how topotecan induces free radical-dependent oxidative stress in tumor cells. In this report we describe the formation of a topotecan radical, catalyzed by a peroxidase-hydrogen peroxide system. While this topotecan radical did not undergo oxidation-reduction with molecular O2, it rapidly reacted with reduced glutathione and cysteine, regenerating topotecan and forming the corresponding glutathiyl and cysteiniyl radicals. Ascorbic acid, which produces hydrogen peroxide in tumor cells, significantly increased topotecan cytotoxicity in MCF-7 tumor cells. The presence of ascorbic acid also increased both topoisomerase I-dependent topotecan-induced DNA cleavage complex formation and topotecan-induced DNA double-strand breaks, suggesting that ascorbic acid participated in enhancing DNA damage induced by topotecan and that the enhanced DNA damage is responsible for the synergistic interactions of topotecan and ascorbic acid. Cell death by topotecan and the combination of topotecan and ascorbic acid was predominantly due to necrosis of MCF-7 breast tumor cells.

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“…Qazi Mohammad Sajid Jamal* of TTOP-IIA has been reported. Due to this characteristic, it can be utilized as a biomarker for the diagnosis of different types of cancer (Pommier et al, 1994;Yousaf et al, 2015). This study presented the topoisomerase integration and analysis to explore the understanding of TTOP-IIA in various carcinomas.…”

Section: Structural Recognition and Binding Pattern Analysis Of Humanmentioning

confidence: 99%

Structural Recognition and Binding Pattern Analysis of Human Topoisomerase II Alpha with Steroidal Drugs: In Silico Study to Switchover the Cancer Treatment

Jamal

2020

Asian Pac J Cancer Prev

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1995). The TTOP-I cuts single-stranded DNA without the expenditure of ATP (Lin et al., 2014), while topoisomerase-II cuts DNA from double-strand with the use of ATP. TTOP-IIA catalyzes a cut on the 3′ end of DNA, while TTOP-IIB catalyzes by covalently linked to the 5' end of the DNA (Pommier et al., 1994). The topoisomerase IA is associated with dividing the nature of the cells, while Topo B is found in neuron and not associated with dividing the nature of the cells. According to previously published research, TTOP-I is associated with cancer, and TTOP-II plays a significant role in cancer development. Thus, these enzymes contribute much more for cancer detection and treatment (Pommier et al., 1998; Andoh and Ishida 1998; Nitiss 2009). TTOP-IIA is widely used as a significant cancer therapeutic because of its involvement with cell proliferation. In many cancer cells, the divergent expression

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Mechanisms of topoisomerase I inhibition by anticancer drugs

Cited by 12 publications

References 167 publications

Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies

Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies

Synergistic enhancement of topotecan-induced cell death by ascorbic acid in human breast MCF-7 tumor cells

Structural Recognition and Binding Pattern Analysis of Human Topoisomerase II Alpha with Steroidal Drugs: In Silico Study to Switchover the Cancer Treatment

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