UNIVERSITY OF MALTA
LIFE SCIENCE RESEARCH SEMINARS
Web: http://www.um.edu.mt/events/scisem/
Email: scisem@um.edu.mt
Abstract form
Title: Identification of novel drug combinations to synergistically target
molecular pathways in breast and prostate cancer
Presenter: Vanessa Petroni
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Presentation date:
‘The Hollies’ Triq L-Istazzjon Birkirkara BKR 1830
(00356) 99 23 23 48
vanessa.petroni.07@um.edu.mt
28th April 2013
Abstract
Background: Breast cancer is one of the most common cancers worldwide, and the first-leading
cause of cancer deaths in women.1 In developed countries, prostate cancer is the principle cause of
cancer mortality in men.2 This research investigates specific molecular mechanisms of drug-induced
cell death, and measures the effectiveness of an optimum drug combination designed to target these
mechanisms.
The proposed synergistic combination includes isoprenoids or statins with (a) rapamycin, or (b)
metformin, both of which inhibit the kinase mammalian Target Of Rapamycin (mTOR),3,4, which is an
important regulator of mRNA translation. Isoprenoids and statins inhibit 3-hydroxy-3methylglutarylCoA reductase (HMG CoA Redutase; HMGCR), the rate limiting enzyme in the farensyl
pathway.5,6,7 Isoprenoids are poorly tolerated8 and tstains are associated with higher muscle toxicity
upon dose increase.9
Methods: Concentration and induction period assessment of rapamycin and metformin, followed by
isoprenoid and statins are being identified by viability assays. Annexin V and PI staining is measuring
the efficacy of various drug/dose combinations, whilst flow cytometry is measuring cell viability
decline, and the appearance of early apoptotic/late apoptotic cells. Western blot analysis is
determining the activity levels of the drug targets. Alternative mechanisms to apoptosis will be
investigated by quantitative PCRs. The results will then be used to confirm data using ex-vivo and invivo techniques.
Results: Results collected from prostate cancer cell lines indicate that LNCaP cells are more
sensitive to metformin than PC-3 cells, whilst PC-3 cells are more sensitive to rapamycin. The
comparison of rapamycin sensitivities among breast cancer cells indicates that Hs587T is the most
sensitive, followed by MDA-MB-436 and BT-20.
Conclusions: Response to Mtor modulators is dependent on time, cell type and dose. Isoprenoid
and statin toxicity profiles shall be improved via the reduction of effective doses, following cellular
pre-treatment. Drug combinations therapeutically targeting two mechanisms converging on a
common target will provide a higher efficacy, allow use of lower individual doses and thus decrease
unwanted effects compared to using either drug alone.
References
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Ahmadinejad N, Movahedinia S, Movahedinia S, Naieni HK, Nedjat S. 2013. Distribution of Breast Density in Iranian Women and its Association with
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British Medical Association. The Royal Pharmaceutical Society of Great Britain. British National Formulary, Number 63. 2012; pp 169