Nanoparticle-induced chemoresistance: the emerging modulatory effects of engineered nanomaterials on human intestinal cancer cell redox metabolic adaptation

• Published in: Nanoscale 2022-10, Vol.14 (39), p.14491-1457
• Main Authors: Wu, Zhuoran, Setyawati, Magdiel Inggrid, Lim, Hong Kit, Ng, Kee Woei, Tay, Chor Yong
• Format: Article
• Language: English
• Subjects: Bioinformatics; Coating effects; Colon; Colorectal cancer; Doxorubicin; Food; Gastrointestinal system; Nanomaterials; Nanoparticles; Silicon dioxide; Spheroids; Stress propagation; Titanium dioxide; Zinc oxide
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/d2nr03893e

The widespread use of engineered nanomaterials (ENMs) in food products necessitates the understanding of their impact on the gastrointestinal tract (GIT). Herein, we screened several representative food-borne comparator ENMs ( i.e. ZnO, SiO 2 and TiO 2 nanoparticles (NPs)) and report that human colon cancer cells can insidiously exploit ZnO NP-induced adaptive response to acquire resistance against several chemotherapeutic drugs. By employing a conditioning and challenge treatment regime, we demonstrate that repeated exposure to a non-toxic dose of ZnO NPs (20 μM) could dampen the efficacy of cisplatin, paclitaxel and doxorubicin by 10-50% in monolayer culture and 3D spheroids of human colon adenocarcinoma cells. Structure-activity relationship studies revealed a complex interplay between nanoparticle surface chemistry and cell type in determining the chemoresistance-inducing effect, with silica coated ZnO NPs having a negligible influence on the anticancer treatment. Mechanistically, we showed that the pro-survival paracrine signaling was potentiated and propagated by a subset of ZnO NP "stressed" (Zn 2+ +/ROS+) cells to the surrounding "bystander" (Zn 2+ +/ROS−) cells. Transcriptome profiling, bioinformatics analysis and siRNA gene knockdown experiments revealed the nuclear factor erythroid 2-related factor 2 (Nrf2) as the key modulator of the ZnO NP-induced drug resistance. Our findings suggest that a ROS-inducing ENM can emerge as a nano-stressor, capable of regulating the chemosensitivity of colon cancer cells. Exposure to non-cytotoxic doses of engineered nanomaterials induce reactive oxygen species stress response cascades in human intestinal cancer cells to resist chemotherapeutics.