Assessment of a Polyfl-uorinated and Platinum-Based Analogue against Triple-Negative Breast Cancer Tzu Chun Kan (1), Sonjid Orchirbat (2), Jungshan Chang (1,2,3*)
1) Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
2) International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
3) International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
* Correspondence
Abstract
Breast cancer is the most common cause of deaths in women suffered from cancers in the 20th century. Especially in patients with triple-negative breast cancer (TNBC), they displayed higher recurrence rate and more aggressive stage after diagnosis. DNA-damaging agents, such as cisplatin, served as a successful approach against breast cancer. However, drug resistance has been reported in clinical practice after a long-term course of treatments. To investigate a new medicine with the improved therapeutic efficacy and declined side effects, we performed a new platinum-based compound with polyfluorinated modification and bipyridine structure in this study. The anti-cancer effects of the potential candidate, dichloro [4,4^-bis(2,2,3,3-tetrafluoropropoxy) methyl)-2,2^-bipryridine] platinum (TFBPC), were majorly determined in MDA-MB-231 human breast cancer cells and xenograft models. Results demonstrated that TFBPC targeting to calf-thymus DNA and circular plasmids resulted in the formation of DNA crosslinks, DNA degradation and cell death program through PARP/Bax/Bcl-2 apoptosis and LC3-related autophagy pathway. In cell line-derived xenograft models, TFBPC significantly inhibited tumor growth without the induction of pathological changes in hematological and biochemistry tests. TFBPC also decreased the expressions of P53, Ki-67 and PD-L1 and increased cleaved caspase 3 expressions in tumors. These results revealed a new achievement to overcome cisplatin resistance and to be a potential strategy in patients with triple-negative breast cancer. For further investigations, details in drug-DNA interaction and pharmacokinetics could be conducted.
Keywords: cisplatin- xenograft model- triple-negative breast cancers- apoptosis- autophagy
