Molecular targets, Patient-derived organoids, Patient-derived xenograft models, Tumor microenvironment, Experimental Therapeutics, Urological Cancers
Dr. Zi combines knowledge in population science with laboratory skills in basic science to develop clinically useful and less or non-toxic bioactive agents from edible plant products for cancer prevention and treatment. His publications identifying silibinin as a strong antiproliferative and differentiate agent for prostate cancer cells have resulted in a Phase 2 clinical trial of silibinin in prostate cancer patients. His NIH funded research discovered that lycopene supplementation can enhance anti-tumor efficacy of docetaxel in prostate cancer mouse xenograft model. The study on lycopene and docetaxel combination in treatment of castration-resistant prostate cancer is also now in Phase I clinical trial at the UCI.
Dr. Zi’s research team studies the efficacy and mechanism of active components of the Kava plant for prevention of tobacco-related bladder cancer using mouse carcinogenesis models. They are developing Ultra Performance Liquid Chromatograph (UPLC)-MS/MS, Chip-sequence, microarray and other molecular biology techniques (e.g., transfection and RNA interference) to study the role of tobacco-related bladder carcinogens and Kava chemicals in histone lysine methylation and epigenetic gene regulation, leading to carcinogenic and anti-carcinogenic effects.
Dr. Zi’s research team also investigates the role of Wnt signaling pathway in the resistance of anti-angiogenic cancer therapy and examine the usefulness of secreted Wnt antagonists for improving the efficacy of bevacizumab in treatment of prostate cancer.
Zi X, Grasso AW, Kung H-J, Agarwal R. A flavonoid antioxidant silymarin inhibits activation of erbB1 signaling, and induces cyclin-dependent kinase inhibitors, G1 arrest and anti-carcinogenic effects in human prostate carcinoma cells DU145. Cancer Res, 58:1920-1929, 1998.
Zi X, Agarwal R. Silibinin decreases prostate specific antigen levels with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: Implications for prostate cancer intervention. Proc Natl Acad Sci USA, 96: 7490-7495, 1999.
Zi X, Zhang J., Agarwal R, Pollak M. Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells Cancer Res 60:5617-20, 2000.
Zi X, Singh RP, Agarwal R. Impairment of erbB1 receptor and fluid-phase endocytosis and associated mitogenic signaling by inositol hexaphosphate in human prostate carcinoma DU145 cells. Carcinogenesis, 21:2225-35. 2000.
Lu Y, Zi X, Zhao Y, Pollak M. Insulin-like growth factor-I receptor signalling and resistance to transtuzumab (Herceptin). J Natl Cancer Inst 93:1852-7, 2001.
Lu Y, Zi X, Pollak M. Molecular mechanisms underlying IGF-I-induced attenuation of the growth inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int J Cancer 108:334-41, 2004.
Lu Y, Zi X, Zhao Y, Pollak M. Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells. Biochem Biophys Res Commun 313: 709-715, 2004.
Zi X, Simoneau A. Flavokawain A, a novel chalcone from Kava Extract, induces apoptosis in bladder cancer cells by involvement of bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice. Cancer Res 65: 3479-3486, 2005.
Zi X, Guo Y, Simoneau A, Christopher H, Xie J, Holcombe RH, Hoang BH. Expression of Frzb/sFRP3, a secreted Wnt antagonist, in an androgen-independent prostate cancer cellular model suppresses tumorigenesis and invasiveness. Cancer Res. 65:9762-70, 2005Liu B, Lee KW, Anzo M, Zhang B, Zi X, Tao Y, Shiry L, Pollak M, Lin S, Cohen P. Insulin-like growth factor-binding protein-3 inhibition of prostate cancer growth involves suppression of angiogenesis. Oncogene 26:1811-9, 2007.
Guo Y, Zi X, Koontz Z, Kim A, Xie J, Gorlick R, Holcombe RF, Hoang BH. Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells. J Orthop Res 25: 964-71, 2007.
Tang Y, Simoneau AR, Xie J, Shahandeh B, Zi X. Flavokawain A, a novel chalcone from Kava extract, differentially induces G1 and M phase arrests in human urinary bladder cancer cell lines associated with their p53 status. Cancer Prev Res (Phila Pa). 1:439-51, 2008 .
Guo Y, Xie J, Rubin E, Zi X, Hoang BH. Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Soft Tissue Sarcoma Cells, Associated with Inhibition of Met Signaling. Cancer Res 68: 3350-60, 2008.
Guo Y, Xie J, Rubin E, Zi X, Hoang BH. Dominant Negative LRP5 Decreases Tumorigenicity and Metastasis of Osteosarcoma. Clinical Orthopaedics and Related Research 466:2039-45, 2008.
Tang Y, Simoneau AR, Liao W, Guo Y, Hoang BH, Hope C, Liu F, Li S, Xie J, Holcombe RF, Jurnak FA, Mercola D, Zi X. WIF-1, a Wnt pathway inhibitor, inhibits the in vitro and in vivo growth of human invasive urinary bladder cancer cells by induction of G1 arrest. Mol Cancer Ther 8:458-68, 2009
Tang Y, Li X, Liu Z, Simoneau AR, Xie J, Zi X. Flavokawain B, a kava chalcone, exhibits robust apoptotic mechanisms on androgen receptor-negative, hormone-refractory prostate cancer cell lines and reduces tumor growth in a preclinical model. Int J Cancer 2010;127:1758-68. PMCID: PMC Journal – In Process.
Rubin E, Guo Yi, Tu K, Xie J, Zi X, Hoang BH. Wnt Inhibitory Factor 1 (WIF-1) decreases tumorigenesis and metastasis in osteosarcoma. Mol Cancer Ther 2010 9:731-41. PMCID: PMC Journal – In Process.
Yee DS, Tang Y, Li X, Liu Z, Guo Y, Ghaffar S, McQueen P, Atreya D, Xie J, Simoneau AR, Hoang BH, Zi X. The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition. Mol Cancer 2010;9:162.
Tang Y, Simoneau AR, Parmakhtiar B, Simoneau AR, Xie J, Fruehauf J, Lilly M, Zi X. Lycopene enhances docetaxel’s effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia 2011;13:108-19.
Liu Z, Li X, Simoneau AR, Jafari M, Zi X. Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy. Mol Carcinog 2011 [Epub ahead of print]
Li X, Liu Z, Xu X, Blair CA, Sun Z, Xie J, Lilly, MB, Zi X. Kava components down-regulate expression of androgen receptor (AR) and AR splice variants and reduce growth in patient-derived prostate cancer xenografts in mice. Plos One 2012;7(2):e31213.
Liu Z, Xu X, Li X, Liu S, Simoneau AR, He F, Wu XR, Zi X. Kava chalcone, flavokawain A, inhibits urothelial tumorigenesis in the UPII-SV40T transgenic mouse model. Cancer Prev Res (Phila). 2013; 6:1365-75.
Zheng YC, Duan YC, Ma JL, Xu RM, Zi X, Lv WL, Wang MM, Ye XW, Zhu S, Mobley D, Zhu YY, Wang ZR, Zhao W, Liu HM. Triazole-Dithiocarbamate Based Selective Lysine Specific Demethylase 1 (LSD1) Inactivators Inhibit Gastric Cancer Cell Growth, Invasion, and Migration. J Med Chem. 2013; 56:8543-60.
Liu Z, Yokoyama NN, Blair CA, Li X, Avizonis D, Wu XR, Uchio E, Youssef R, McClelland M, Pollak M, Zi X. High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin Is Associated with ~240-Fold Higher Drug Concentration in Urine than Serum. Mol Cancer Ther. 2016;15: 430-8.
Chen L, Xia G, Qiu F, Wu C, Denmon AP, Zi X. Physapubescin selectively induces apoptosis in VHL-null renal cell carcinoma cells through down-regulation of HIF-2a and inhibits tumor growth. Sci Rep. 2016;6:32582.
Wang W, Qin JJ, Li X, Tao G, Wang Q, Wu X, Zhou J, Zi X, Zhang R. Prevention of prostate cancer by natural product MDM2 inhibitor GS25: In vitro and in vivo activities and molecular mechanisms. Carcinogenesis. 2018 39:1026-1036.
Pham V, Rendon R, Le VX, Tippin M, Fu DJ, Le TH, Miller M, Agredano E, Cedano J, Zi X. Gartanin Is a Novel NEDDylation Inhibitor for Induction of Skp2 Degradation, FBXW2 Expression, and Autophagy. Mol Carcinog. 2020; 59, 193-201,
1.5R01CA193967-03 (ZI) 07/01/2016-06/30/2021
NIH/NCI $239,839 (direct) /annual Total (direct and indirect): $1,776,560
Title: The NEDD8 pathway mediated Skp2 degradation in chemoprevention by FKA
The major goals of this project are to 1) Define mechanisms of FKA mediated Cullin1 deNEDDylation and Skp2 degradation; 2) Test the hypothesis that accumulation of Skp2 substrates is required for FKA mediated cell growth inhibition via cell cycle arrest and induction of apoptosis; 3) Perform pharmacokinetic/pharmacodynamics (PK/PD) and in vivo mechanistic studies on FKA mediated Skp2 degradation.
2. PC181016 (Zi) 09/30/2019-09/29/2022 DOD/Prostate Cancer Research Program Total (direct and indirect): $1,407,580
Title: Carcinoma-Associated Fibroblasts from African American Prostate Cancer Promote Aggressive
Tumors: Implications for Developing Novel Therapy
The major goals of this project are determine the differential ability of African American (AA) tumor-adjacent cancer-associated fibroblasts (CAFs) vs. European American (EA) CAFs to transform BPH-1 cells and the normal mouse prostate into tumorigenic products; Determine the impact of the enzymatic activity or expression of PSPH and high serine production on in vivo tumor growth; and 3) Develop a tumor microenvironment-responsive nanoparticle drug for prostate cancer with dense extracellular matrix and reactive stroma.
3. 1R01CA226570-01A1 (Rahmatpanah) 04/03/2019-03/31/2024 NIH/NCI $228,750 (direct) /annual Total (direct and indirect): $1,767,095
Title: Aggressive prostate cancer of African Americans is correlated with regulation of Immunoregulatory Genes in stroma
The major goals of this project are to 1) Investigate whether 5AzaC and/or type 1 IFN enhance the activity of interferon-stimulated genes (ISGs) in tumor-adjacent cancer-associated fibroblasts (CAFs) of African American (AA) and European American (EA); 2) Explore whether dendritic cells (DCs) co-cultured with AA CAFs and EA CAFs display differences in IFN production and T-cell activation; 3) Investigate protein markers for endogenous retroviruses, IFNs, ISGs, and activated DCs by immunohistochemistry of tumor samples.
4. I01BX005105 (ZI) 10/01/2021 - 09/30/2025 VA Merit Award Amount: $1,079,938.0
Title: A novel targetable mechanism for castration-resistant prostate cancer
The major goals of this project are 1) test the hypothesis that srGAP1 is one of the required down-stream intermediates for progression to CRPC and for resistance to anti-androgen therapies. 2) determine the impact of functional domains and GTPase activity of srGAP1 on AR and Wnt/?-catenin signaling and on biological behaviors of CRPC, and 3) determine pathophysiological relevance of the interplay among Slit/Robo/srGAP1, AR and Wnt signaling and whether the expression of srGAP1 will be a good predictor for disease progression and overall survival of CRPC patients.
Medicinal Chemistry and Pharmacology
Chao Family Comprehensive Cancer Center