title: Tumor growth and metastasis can be inhibited by maintaining genomic stability in cancer cells.
abstract: The existence of cancer stem cells, stem-like cancer cells (SLCCs), or tumor-initiating cells is considered as the cause of tumor formation and recurrence, indicating the importance of studying novel therapy that targets SLCCs. The origin of SLCCs is controversial because of two competing hypotheses: SLCCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Our previous research demonstrates that SLCCs are inducible by increasing genomic instability in cancer cells. In this study, to block the emergence of SLCCs, aminoethyl isothiourea (AET), a compound that clears free radicals and is used to protect patients from radioactive exposure, was used as an agent that maintains genomic stability in combination with mitomycin C (MMC), a commonly used chemotherapeutic drug that damages DNA. Using a rabbit tumor model with VX2 hepatic carcinoma, we found that MMC alone increased lung metastases and disadvantaged survival outcome, but the combination of MMC and AET reversed this effect and even prolonged overall survival. Moreover, in a VX2 xenograft model by immunocompromised mice, MMC alone enriched tumor-initiating cells, but the administration of MMC in combination with AET eliminated tumor cells effectively. Furthermore, MMC alone enhanced genomic instability, but MMC combined with AET attenuated the extent of genomic instability in primary VX2 tumor tissue. Taken together, our data suggest that the genomic protector AET can inhibit the induction of SLCCs, and this combination treatment by AET and cytotoxic agents should be considered as a promising strategy for future clinical evaluation.
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors: Yi
authors: Y
authors: Liang
authors: Qisheng
authors: Q
authors: Feng
authors: Jian
authors: J
authors: Hong
authors: Futuo
authors: F
authors: Feng
authors: Yi
authors: Y
authors: Sang
authors: Wenrong
authors: W
authors: Hu
authors: Miao
authors: M
authors: Xu
authors: Roujun
authors: R
authors: Peng
authors: Tiebang
authors: T
authors: Kang
authors: Jinxin
authors: J
authors: Bei
authors: Yixin
authors: Y
authors: Zeng
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology*; D009385:Neoplastic Processes; D014411:Neoplastic Stem Cells / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011817:Rabbits; D011837:Radiation-Protective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; C413842:aminoethyl-isothiourea; D016685:Mitomycin; D019001:Nitric Oxide Synthase; D013890:Thiourea