Ldrb toxin with in vitro and in vivo antitumor activity as a potential tool for cancer gene therapy
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AuthorJiménez Martínez, Yaiza; Griñán Lisón, Carmen; Khaldy Belkadi, Hoda; Martín, Ana; Cambrils, Alba; Ibáñez Grau, Andrea; Jiménez, Gema; Marchal Corrales, Juan Antonio; Boulaiz Tassi, Houria
Suicide gene therapyLdrB geneColorectal cancerbreast cancerApoptosisCell cycle arrest
Jiménez-Martínez Y, Griñán-Lisón C, Khaldy H, et al. LdrB Toxin with In Vitro and In Vivo Antitumor Activity as a Potential Tool for Cancer Gene Therapy. Cancers (Basel). 2019;11(7):1016. Published 2019 Jul 20. [doi:10.3390/cancers11071016]
SponsorshipThis research was supported by the Fundación Mutua Madrileña (project FMM-AP16683-2017), Consejería de Salud Junta de Andalucía (PI-0089-2017), the MNat Scientitc Unit of Excellence (UCE.PP2017.0f), and from the Chair “Doctors Galera-Requena in cancer stem cell research”.
Due to the high prevalence of cancer in recent years, it is necessary to develop new and more effective therapies that produce fewer side effects. Development of gene therapy for cancer based on the use of suicide genes that can damage the tumor cell, without requiring a prodrug for its lethal effect, is one of the recent foci of gene therapy strategies. We evaluated the cytotoxic impact of the LdrB toxin from Escherichia coli k12 as a possible tool for cancer gene therapy. For that, colorectal and breast cancer cells were transfected under the control of a TRE3G promoter inducible by doxycycline. Our results showed that ldrB gene expression induced a drastic inhibition of proliferation in vitro, in both 2D and 3D experimental models. Moreover, unlike conventional chemotherapy, the ldrB gene induced a severe loss of proliferation in vivo without any side effects in our animal model. This antitumor outcome was modulated by cell cycle arrest in the G0/G1 phase and apoptotic death. Scanning electronic microscopy demonstrates that the LdrB toxin conserves its pore-forming ability in HCT-116 cells as in E. coli k12. Taken together, our results provide, for the first time, a proof of concept of the antitumor capacity of the ldrB gene in colorectal and breast cancer.