Book of Abstracts - Ruhr-Universität Bochum

P-81
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Apoptosis induction and cytotoxicity by metalbased drugs:
lights and shadows of DNA
Gianni Sava a,b and Alberta Bergamo b
a University of Trieste, Department of Life Sciences, via L. Giorgieri 7, 34127, Trieste, Italy. b Callerio
Foundation Onlus, via A. Fleming 22-31, 34127, Trieste, Italy. E-mail: gsava@units.it
Cisplatin is a well known DNA-damaging agent and the current thinking is that DNA platination
(DNA-adduct formation) is an essential first step in the cytotoxic activity of the drug. Information
about the chemistry of the platinum compounds and correlations of their structures with anticancer
activity have provided guidance for the design of novel anticancer drug candidates based on the
proposed mechanisms of action. 1 The question is: DNA-adduct formation guided synthesis of metalbased
anticancer drugs is a real concept or a misleading interpretation? The mechanism(s) whereby the
DNA adducts kill cells is not fully understood. One potentially important way by which cisplatin-
DNA adducts may kill cells is by induction of programmed cell death or apoptosis (Figure 1). 2,3
From: to:
Figure 1. types of DNA adduct formation of platinum drugs: (a) interstrand cross-link, (b) 1,2intrastrand
cross-link, (c) 1,3-intrastrand crosslink, (d) protein-DNA cross-link (adapted from Lit. 2)
However, these concepts are not sufficient to account for the particular effectiveness of the most
important platinum drugs in cancer therapy where cisplatin and carboplatin (two drugs with a rather
different chemistry) are active on the same tumours, oxaliplatin is active on colorectal tumours and
satraplatin (the emerging oral platinum drug) is active on prostate cancer. None of these tumours were
selected a priori as the targets for these drugs. Then, how focusing on the ligands that allow DNA
binding or to get insensitivity to acquired resistance, may help researchers to understand what to take
into consideration to design the expected more potent, more selective and less toxic new metal-based
antitumour drugs? Apoptosis and cell death is not simply related to DNA binding properties as shown
by the many biological and targeted drugs emerged in the last years which killed cells by apoptoptic
mechanisms following interactions with protein components of important cellular pathways. Given
that cisplatin and also many platinum drugs have a poor capacity to enter the nucleus compartment (in
the case of cisplatin almost 99% of the cellular drug is in the cytoplasm) the focus should be directed
on what are the final destinations of all these platinum molecules in this protein-rich compartment. As
an example, interesting data are emerging on HSP90 block by cisplatin, a phenomenon that could
account for many apoptotic cytotoxicities observed. This work was done in the framework of COST
D39 – WG3.
References
1. K.S. Lovejoy, S.J. Lippard, Dalton Trans. 2009, 48, 10651-10659.
2. A. Eastman: The mechanism of action of cisplatin: From adducts to apoptosis in: Cisplatin.
Chemistry and Biochemistry of a Leading Anticancer Drug; B. Lippert, Ed.; Wiley-VCH: Basel,
Switzerland, 1999, pp. 111–134.
3. R.C. Todd, S.J. Lippard, Metallomics 2010, 4, 280-291.
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