Topoisomerase I poisons-induced autophagy: Cytoprotective, Cytotoxic or Non-protective

Figures & data

Figure 1. The mechanism of action of topoisomerase I inhibitors. Irinotecan and topotecan exert their antitumor effects via covalent binding with topoisomerase I, resulting in Top I- Irinotecan/Topotecan-DNA complex formation. This complex generates single and double-strand breaks in DNA, leading to cell death.

Figure 2. Top I inhibition triggers autophagy via m-TOR suppression. Topoisomerase I inhibition by irinotecan or topotecan generates reactive oxygen species (ROS), which drives the activation of JNK/AMP and p38/MAPK. JNK phosphorylation activates SESN2, followed by AMPK. p38 activation via ROS upregulates MAPK. These two pathways converge on m-TOR, where m-TOR inhibition triggers autophagic flux.

Table 1. Various functions of autophagy in response to the clinically used topoisomerase I inhibitors.

Compound	Cancer type/ cell line	Autophagy Modulation	Autophagy function	References
Irinotecanmetabolite, SN-38	LOVO and HCT116, SW1116 colorectal cancer cell lines and the overexpressing mutant p53 SW480 and HT-29 colorectal cancer cell lines	3-MA, CQ, ATG5 siRNA	Non-protective	[40]
NA	Irinotecan-resistant LOVO colon cancer cell line	N/A	High level of basal autophagy in these cell line	[41]
Irinotecan metabolite, SN-38	HSC-4 and HSC-2 human oral squamous cell carcinoma cell line	3-MA, Baf A1	Cytotoxic in HSC-4, however; non-protective in HSC-2	[42]
Irinotecan	MGC803 and SGC7901 gastric cancer cells lines	3-MA, CQ, Beclin1 siRNA	Cytotoxic	[36]
Irinotecan metabolite, SN-38	MDA-MB-231 and MDA-MB-436 triple-negative breast cancer cell lines	Baf A1, CQ, toosendanin (TSN)	Cytoprotective	[43]
Irinotecan metabolite, SN-38	HCT116-TP53 KO colon cancer cell line	Baf A1, 3-MA, ATG5 siRNA, ATG7 siRNA	Cytoprotective	[44]
Topotecan	A549 non-small cell lung cancer cell line	CQ, ATG5 siRNA	Cytoprotective	[45]
Topotecan	P53 wild-type (HCT116 and LS-174T) and p53 mutant (HT29, SW620, HCT116 p53^−/− and SW480) human colon cancer cell lines	Beclin1 siRNA, ATG-5 siRNA, CQ	Cytoprotective	[51]

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