Resume

• 2010

  Jeremy J.

  Johnson

  PharmD

  PhD

  University of Illinois at Chicago

  Characterization of natural products from for cancer chemoprevention and/or chemotherapy with an emphasis on translating promising natural compounds.\n\nPre-clinical Research: mechanistic studies

  in vivo efficacy

  animal pharmacokinetics\n\nClinical Research: Phase I clinical trials

  University of Illinois at Chicago

  University of Illinois at Chicago

  Chicago

  IL

  Clinical Pharmacist

• 2007

  University of Wisconsin-Madison

  University of Illinois at Chicago

  Assistant Head for Research (Pharmacy Practice)

  University of Illinois at Chicago

  University of Wisconsin-Madison

  MERIT Award - National Cancer Institute

  National Cancer Institute

  PhD

  Biomedical Sciences

• 2003

  PharmD

  Pharmacy

• 1997

  BS

  Biology and Chemistry

  University of Wisconsin-Stevens Point

• 5

  SCOPE: Resveratrol (3

  4'-trihydroxystilbene) is a phytoalexin shown to possess a multitude of health-promoting properties in pre-clinical studies. However

  the poor in vivo bioavailability of resveratrol due to its rapid metabolism is being considered as a major obstacle in translating its effects in humans. In this study

  we examined the hypothesis that piperine will enhance the pharmacokinetic parameters of resveratrol via inhibiting its glucuronidation

  thereby slowing its elimination.\nMETHODS AND RESULTS: Employing a standardized LC/MS assay

  we determined the effect of piperine co-administration with resveratrol on serum levels resveratrol and resveratrol-3-O-β-D-glucuronide in C57BL mice. Mice were administered resveratrol (100 mg/kg; oral gavage) or resveratrol (100 mg/kg; oral gavage)+piperine (10 mg/kg; oral gavage)

  and the serum levels of resveratrol and resveratrol-3-O-β-D-glucuronide were analyzed at different times. We found that the degree of exposure (i.e. AUC) to resveratrol was enhanced to 229% and the maximum serum concentration (C(max)) was increased to 1544% with the addition of piperine.\nCONCLUSION: Our study demonstrated that piperine significantly improves the in vivo bioavailability of resveratrol. However

  further detailed research is needed to study the mechanism of improved bioavailability of resveratrol via its combination with piperine as well as its effect on resveratrol metabolism.

  Enhancing the bioavailability of resveratrol by combining it with piperine.

  Pharmacokinetic characterization of mangosteen (Garcinia mangostana) fruit extract standardized to α-mangostin in C57BL/6 mice.

  Previously

  we have reported the pharmacokinetic (PK) properties of α-mangostin in mice. For this study

  we evaluated the PK profile of α-mangostin using a standardized mangosteen extract in C57BL/6 mice. The primary objective was to determine the PK properties of α-mangostin when administered as an extract. This experiment was designed to test our primary hypothesis that α-mangostin in an extract should achieve a desirable PK profile. This is especially relevant as dietary supplements of mangosteen fruit are regularly standardized to α-mangostin. Mice received 100 mg/kg of mangosteen fruit extract orally

  equivalent to 36 mg/kg of α-mangostin

  and plasma samples were analyzed over a 24-hour period. Concentrations of α-mangostin were determined by liquid chromatography-tandem mass spectrometry. In addition

  we evaluated the stability in the presence of phase I and phase II enzymes in liver and gastrointestinal microsomes. Furthermore

  we identified evidence of phase II metabolism of α-mangostin. Further research will be required to determine if less abundant xanthones present in the mangosteen may modulate the PK parameters of α-mangostin.

  Pharmacokinetic characterization of mangosteen (Garcinia mangostana) fruit extract standardized to α-mangostin in C57BL/6 mice.

  Johnson

  PharmD

  PhD

• Androgen deprivation therapy in prostate cancer is extremely effective; however

  due to the continuous expression and/or mutagenesis of androgen receptor (AR)

  the resistance to antihormonal therapy is a natural progression. Consequently

  targeting the AR for degradation offers an alternate approach to overcome this resistance in prostate cancer. In this study

  we demonstrate that carnosic acid

  a benzenediol diterpene

  binds the ligand-binding domain of the AR and degrades the AR via endoplasmic reticulum (ER) stress-mediated proteasomal degradative pathway. In vitro

  carnosic acid treatment induced degradation of AR and decreased expression of prostate-specific antigen in human prostate cancer cell lines LNCaP and 22Rv1. Carnosic acid also promoted the expression of ER proteins including BiP and CHOP in a dose-dependent manner. Downregulation of CHOP by small interfering RNA somewhat restored expression of AR suggesting that AR degradation is dependent on ER stress pathway. Future studies will need to evaluate other aspects of the unfolded protein response pathway to characterize the regulation of AR degradation. Furthermore

  cotreating cells individually with carnosic acid and proteasome inhibitor (MG-132) and carnosic acid and an ER stress modulator (salubrinal) restored protein levels of AR

  suggesting that AR degradation is mediated by ER stress-dependent proteasomal degradation pathway. Degradation of AR and induction of CHOP protein were also evident in vivo along with a 53% reduction in growth of xenograft prostate cancer tumors. In addition

  carnosic acid-induced ER stress in prostate cancer cells but not in normal prostate epithelial cells procured from patient biopsies. In conclusion

  these data suggest that molecules such as carnosic acid could be further evaluated and optimized as a potential therapeutic alternative to target AR in prostate cancer.

  Carnosic acid promotes degradation of the androgen receptor and is regulated by the unfolded protein response pathway in vitro and in vivo

  The mangosteen (Garcinia mangostana) fruit has been a popular food in Southeast Asia for centuries and is increasing in popularity in Western countries. We identified α-Mangostin as a primary phytochemical modulating ER stress proteins in prostate cancer cells and propose that α-Mangostin is responsible for exerting a biological effect in prostate cancer cells. Two human prostate cancer cell lines

  22Rv1 and LNCaP

  and prostate epithelial cells procured from two patients undergoing radical prostatectomy were treated with α-Mangostin and evaluated by RT-PCR

  Western blot

  fluorescent microscopy and siRNA transfection to evaluate ER stress. Next

  we evaluated α-Mangostin for microsomal stability

  pharmacokinetic parameters

  and anti-cancer activity in nude mice. α-Mangostin significantly upregulated ER stress markers in prostate cancer cells. Interestingly

  α-Mangostin did not promote ER stress in prostate epithelial cells (PrECs) from prostate cancer patients. CHOP knockdown enhanced α-Mangostin-induced apoptosis in prostate cancer cells. α-Mangostin significantly suppressed tumor growth in a xenograft tumor model without obvious toxicity. Our study suggests that α-Mangostin is not the only active constituent from the mangosteen fruit requiring further work to understand the complex chemical composition of the mangosteen.

  Inhibition of CHOP accentuates the apoptotic effect of α-mangostin from the mangosteen fruit (Garcinia mangostana) in 22Rv1 prostate cancer cells.

  Rosemary (Rosmarinus officinalis) extract modulates CHOP/GADD153 to promote androgen receptor degradation and decreases xenograft tumor growth.

  The Mediterranean diet has long been attributed to preventing or delaying the onset of cardiovascular disease

  diabetes and various solid organ cancers. In this particular study

  a rosemary extract standardized to carnosic acid was evaluated for its potential in disrupting the endoplasmic reticulum machinery to decrease the viability of prostate cancer cells and promote degradation of the androgen receptor. Two human prostate cancer cell lines

  22Rv1 and LNCaP

  and prostate epithelial cells procured from two different patients undergoing radical prostatectomy were treated with standardized rosemary extract and evaluated by flow cytometry

  MTT

  BrdU

  Western blot and fluorescent microscopy. A significant modulation of endoplasmic reticulum stress proteins was observed in cancer cells while normal prostate epithelial cells did not undergo endoplasmic reticulum stress. This biphasic response suggests that standardized rosemary extract may preferentially target cancer cells as opposed to \"normal\" cells. Furthermore

  we observed standardized rosemary extract to decrease androgen receptor expression that appears to be regulated by the expression of CHOP/GADD153. Using a xenograft tumor model we observed standardized rosemary extract when given orally to significantly suppress tumor growth by 46% compared to mice not receiving standardized rosemary extract. In the last several years regulatory governing bodies (e.g. European Union) have approved standardized rosemary extracts as food preservatives. These results are especially significant as it is becoming more likely that individuals will be receiving standardized rosemary extracts that are a part of a natural preservative system in various food preparations. Taken a step further

  it is possible that the potential benefits that are often associated with a \"Mediterranean Diet\" in the future may begin to extend beyond the Mediterranean diet as more of the population is consuming standardized rosemary extracts.

  Rosemary (Rosmarinus officinalis) extract modulates CHOP/GADD153 to promote androgen receptor degradation and decreases xenograft tumor growth.

  Standardized rosemary (Rosmarinus officinalis) extract induces Nrf2/sestrin-2 pathway in colon cancer cells

  Rosemary and its polyphenolic diterpene

  carnosic acid

  are known to possess antioxidant activity and are used as a natural antioxidant food preservative. The intake of vegetables and certain plant components has been reported to play a major role in promoting gastrointestinal health. In the current study

  the anticancer activity of rosemary extract and carnosic acid was evaluated to understand the potential implications on gastrointestinal health. We also evaluated the anti-cancer activity of rosemary extract in a nude mouse model. Rosemary extract and carnosic acid

  increased apoptosis

  and decreased viability in colon cancer cell lines. Rosemary extract and carnosic acid significantly upregulated the expression of Nrf2 in colon cells and inhibited a HCT116 xenograft tumor formation in mice. These results are especially significant as rosemary extract is increasingly being incorporated into food products across the United States and Europe as a food preservative.

  Standardized rosemary (Rosmarinus officinalis) extract induces Nrf2/sestrin-2 pathway in colon cancer cells

  Enhancing the bioavailability of resveratrol by combining it with piperine.