Jianling Bi1, Sudartip Areecheewakul2, Yujun Li1, Shujie Yang3, Yuping Zhang1, Kareem Ebeid2, Long Li1, Kristina W Thiel1, Jun Zhang4, Donghai Dai5, Aliasger K Salem6, Kimberly K Leslie5, Xiangbing Meng7. 1. Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. 2. Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA. 3. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; Department of Pathology, University of Iowa, Iowa City, IA 52242, USA. 4. Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical / Cancer Centers, Kansas City, KS 66160. 5. Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA. 6. Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA. 7. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; Department of Pathology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: xiangbing-meng@uiowa.edu.
Abstract
OBJECTIVE: Platinum compounds have been widely used as a primary treatment for many types of cancer. However, resistance is the major cause of therapeutic failure for patients with metastatic or recurrent disease, thus highlighting the need to identify novel factors driving resistance to Platinum compounds. Metadherin (MTDH, also known as AEG-1 and LYRIC), located in a frequently amplified region of chromosome 8, has been consistently associated with resistance to chemotherapeutic agents, though the precise mechanisms remain incompletely defined. METHODS: The mRNA of FANCD2 and FANCI was pulled down by RNA-binding protein immunoprecipitation. Pristimerin-loaded nanoparticles were prepared using the nanoprecipitation method. Immunocompromised mice bearing patient-derived xenograft tumors were treated with pristimerin-loaded nanoparticles, cisplatin and a combination of the two. RESULTS: MTDH, through its recently discovered role as an RNA binding protein, regulates expression of FANCD2 and FANCI, two components of the Fanconi anemia complementation group (FA) that play critical roles in interstrand crosslink damage induced by platinum compounds. Pristimerin, a quinonemethide triterpenoid extract from members of the Celastraceae family used to treat inflammation in traditional Chinese medicine, significantly decreased MTDH, FANCD2 and FANCI levels in cancer cells, thereby restoring sensitivity to platinum-based chemotherapy. Using a patient-derived xenograft model of endometrial cancer, we discovered that treatment with pristimerin in a novel nanoparticle formulation markedly inhibited tumor growth when combined with cisplatin. CONCLUSIONS: MTDH is involved in post-transcriptional regulation of FANCD2 and FANCI. Pristimerin can increase sensitivity to platinum-based agents in tumors with MTDH overexpression by inhibiting the FA pathway.
OBJECTIVE:Platinum compounds have been widely used as a primary treatment for many types of cancer. However, resistance is the major cause of therapeutic failure for patients with metastatic or recurrent disease, thus highlighting the need to identify novel factors driving resistance to Platinum compounds. Metadherin (MTDH, also known as AEG-1 and LYRIC), located in a frequently amplified region of chromosome 8, has been consistently associated with resistance to chemotherapeutic agents, though the precise mechanisms remain incompletely defined. METHODS: The mRNA of FANCD2 and FANCI was pulled down by RNA-binding protein immunoprecipitation. Pristimerin-loaded nanoparticles were prepared using the nanoprecipitation method. Immunocompromised mice bearing patient-derived xenograft tumors were treated with pristimerin-loaded nanoparticles, cisplatin and a combination of the two. RESULTS:MTDH, through its recently discovered role as an RNA binding protein, regulates expression of FANCD2 and FANCI, two components of the Fanconi anemia complementation group (FA) that play critical roles in interstrand crosslink damage induced by platinum compounds. Pristimerin, a quinonemethidetriterpenoid extract from members of the Celastraceae family used to treat inflammation in traditional Chinese medicine, significantly decreased MTDH, FANCD2 and FANCI levels in cancer cells, thereby restoring sensitivity to platinum-based chemotherapy. Using a patient-derived xenograft model of endometrial cancer, we discovered that treatment with pristimerin in a novel nanoparticle formulation markedly inhibited tumor growth when combined with cisplatin. CONCLUSIONS:MTDH is involved in post-transcriptional regulation of FANCD2 and FANCI. Pristimerin can increase sensitivity to platinum-based agents in tumors with MTDH overexpression by inhibiting the FA pathway.
Authors: Somaira Nowsheen; Rebecca L Wukovich; Khaled Aziz; Peter T Kalogerinis; Christopher C Richardson; Mihalis I Panayiotidis; William M Bonner; Olga A Sedelnikova; Alexandros G Georgakilas Journal: Mutat Res Date: 2008-10-02 Impact factor: 2.433
Authors: Kareem Ebeid; Xiangbing Meng; Kristina W Thiel; Anh-Vu Do; Sean M Geary; Angie S Morris; Erica L Pham; Amaraporn Wongrakpanich; Yashpal S Chhonker; Daryl J Murry; Kimberly K Leslie; Aliasger K Salem Journal: Nat Nanotechnol Date: 2017-12-04 Impact factor: 39.213
Authors: Jianling Bi; Yuping Zhang; Paige K Malmrose; Haley A Losh; Andreea M Newtson; Eric J Devor; Kristina W Thiel; Kimberly K Leslie Journal: Cell Death Dis Date: 2022-01-17 Impact factor: 8.469