Parisa Zargar1, Shabnaz Koochakkhani2, Marziyeh Hassanzadeh1, Yaghoub Ashouri Taziani3, Hamid Nasrollahi4, Ebrahim Eftekhar5. 1. Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. 2. Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. 3. Department of Medical Physics, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. 4. Radio-Oncology Department, Shiraz University of Medical Sciences, Shiraz, Iran. 5. Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. eftekhar19@gmail.com.
Abstract
BACKGROUND: Resistance to cisplatin is a major obstacle to effective treatment of bladder cancer (BC). The present study aimed to determine whether a combination of acriflavine (ACF) with cisplatin could potentiate the antitumor property of cisplatin against the BC cells. Furthermore, the molecular mechanism behind the anticancer action of ACF was considered. METHODS AND RESULTS: Two human BC cells (5637 and EJ138) contain mutated form of p53 was culture in standard condition. Cotreatment protocol (simultaneous combination of IC30 value of ACF + various dose of cisplatin for 72 h) and pretreatment protocol (pretreatment with IC15 value of ACF for 24 h + various dose of cisplatin for 48 h) was used to determine the effect of ACF on the cells' sensitivity to main drug cisplatin. To assess the mechanism of action of ACF, real-time PCR was used to evaluate mRNA levels of hypoxia-inducible factor-1α (HIF-1α), Bax, Bcl-2, topoisomerase1 (TOP1) and topoisomerase 2 (TOP2A). Combination of ACF with cisplatin either as cotreatment or opretreatment protocol could significantly reduce the IC50 values of cisplatin as compared to the IC50 of cisplatin when use as a single drug. In addition, ACF could markedly decrease mRNA expression of TOP1 and TOP2A without changing the expression of HIF-1ɑ, Bax and Bcl-2. CONCLUSIONS: Our findings indicate that combination of cisplatin with ACF was able to significantly enhance the sensitivity of BC cells to cisplatin. The antitumor activity of ACF is exerted through the downregulation of TOP1 and TOP2A genes expression. ACF may serve as an adjuvant to boost cisplatin-based chemotherapy.
BACKGROUND: Resistance to cisplatin is a major obstacle to effective treatment of bladder cancer (BC). The present study aimed to determine whether a combination of acriflavine (ACF) with cisplatin could potentiate the antitumor property of cisplatin against the BC cells. Furthermore, the molecular mechanism behind the anticancer action of ACF was considered. METHODS AND RESULTS: Two human BC cells (5637 and EJ138) contain mutated form of p53 was culture in standard condition. Cotreatment protocol (simultaneous combination of IC30 value of ACF + various dose of cisplatin for 72 h) and pretreatment protocol (pretreatment with IC15 value of ACF for 24 h + various dose of cisplatin for 48 h) was used to determine the effect of ACF on the cells' sensitivity to main drug cisplatin. To assess the mechanism of action of ACF, real-time PCR was used to evaluate mRNA levels of hypoxia-inducible factor-1α (HIF-1α), Bax, Bcl-2, topoisomerase1 (TOP1) and topoisomerase 2 (TOP2A). Combination of ACF with cisplatin either as cotreatment or opretreatment protocol could significantly reduce the IC50 values of cisplatin as compared to the IC50 of cisplatin when use as a single drug. In addition, ACF could markedly decrease mRNA expression of TOP1 and TOP2A without changing the expression of HIF-1ɑ, Bax and Bcl-2. CONCLUSIONS: Our findings indicate that combination of cisplatin with ACF was able to significantly enhance the sensitivity of BC cells to cisplatin. The antitumor activity of ACF is exerted through the downregulation of TOP1 and TOP2A genes expression. ACF may serve as an adjuvant to boost cisplatin-based chemotherapy.
Authors: Hans von der Maase; Lisa Sengelov; James T Roberts; Sergio Ricci; Luigi Dogliotti; T Oliver; Malcolm J Moore; Annamaria Zimmermann; Michael Arning Journal: J Clin Oncol Date: 2005-07-20 Impact factor: 44.544
Authors: KangAe Lee; Huafeng Zhang; David Z Qian; Sergio Rey; Jun O Liu; Gregg L Semenza Journal: Proc Natl Acad Sci U S A Date: 2009-10-01 Impact factor: 11.205
Authors: Ruud Weijer; Mans Broekgaarden; Massis Krekorian; Lindy K Alles; Albert C van Wijk; Claire Mackaaij; Joanne Verheij; Allard C van der Wal; Thomas M van Gulik; Gert Storm; Michal Heger Journal: Oncotarget Date: 2016-01-19