Parthenolide in the treatment and prevention of prostate cancer

Author: Katherine Morel

Morel, Katherine, 2017 Parthenolide in the treatment and prevention of prostate cancer, Flinders University, School of Medicine

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Abstract

Prostate cancer is the most commonly diagnosed cancer in Australian men. While significant improvements have been made in prostate therapy, there is still a need for novel treatment options, particularly for preventing and treating metastatic prostate cancer which has a very poor prognosis, and for protecting from debilitating side effects of radiotherapy, where many men suffer side effects due to damage done to healthy tissues near the prostate. Parthenolide is a naturally occurring sesquiterpene lactone derived from the plant feverfew (Tanacetum parthenium) with anti-inflammatory and anti-cancer properties through pro-apoptotic action, stimulation of reactive oxygen species, inhibition of NF-ĸB and its down-stream targets as well as many key proteins important for metastasis. In vitro and xenograft studies indicate that parthenolide holds promise as an anti-cancer agent and also a differential radiosensitiser for prostate cancer. This thesis describes the first examination of the anti-cancer effects of parthenolide (PTL) and dimethylaminoparthenolide (DMAPT), a parthenolide analogue with increased water solubility, in an autochthonous model of prostate cancer (TRAMP, Transgenic Adenocarcinoma of the Mouse Prostate). Treatment of TRAMP mice with DMAPT (100 mg/kg) 3 times per week significantly increased time-to-palpable tumour development by 20% and reduced metastatic spread to the lung by 95%, compared to mice treated with a water vehicle. PTL (40 mg/kg), delivered in a 10% ethanol/saline vehicle, did not slow tumour development. Unexpectedly, the ethanol/saline vehicle induced an aggressive metastatic phenotype in the TRAMP model, in which mice developed large palpable metastatic tumours and small slow-growing primary prostate tumours. This tumour phenotype was counteracted by parthenolide (in ethanol/saline vehicle). The chronic low dose of ethanol increased expression of molecules involved in metastatic spread, MMP2, integrin β1, laminin, fibronectin and collagen IV in primary prostate tumours, all of which were reduced to baseline levels by parthenolide. When TRAMP and C57BL/6J mice were treated with DMAPT (100 mg/kg) or PTL (40 mg/kg) prior to 6 Gy whole body X-radiation, the level of radiation-induced apoptosis observed in vivo was significantly reduced in normal prostate, spleen and colorectal tissue by up to 72%. Pre-treatment with DMAPT doubled the efficacy of prostate tumour cell killing. DMAPT preferentially radiosensitised regions of high grade prostatic intraepithelial neoplasia within TRAMP prostate tissues, suggesting that DMAPT may be particularly able to target regions of higher oxidative stress, as is often observed in high grade metastatic prostate cancers. When DMAPT was combined with a low conditioning dose of radiation there was evidence that this combination might be able to augment the radioprotective effects of DMAPT alone in normal tissues. The results in this thesis provide strong evidence for DMAPT as an anti-cancer and anti-metastatic agent, as well as a differential radiosensitiser in prostate cancer. This work provides the groundwork for future clinical trials to apply DMAPT for improving cure rates and also protecting from unwanted debilitating side-effects from prostate cancer radiotherapy. The mechanisms involved in the anti-cancer and radioprotective effects of parthenolide are not specific to prostate cancer and therefore there is the potential for its use in the treatment of other cancer types as well.

Keywords: prostate, cancer, radiotherapy, parthenolide, DMAPT, radiosensitiser, radioprotector, apoptosis
Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2017
School: School of Medicine
Supervisor: Prof. Pamela Sykes