ANTICANCER RESEARCH 24: 1529-1544 (2004) Review Metals and Metal Compounds in Cancer Treatment BERNARD DESOIZE Laboratoire de Biochimie et de Biologie Moléculaire, EA 3306, IFR 53, Faculté de Pharmacie, 51 rue Cognacq-Jay, 51096 Reims cedex, France Abstract. Metals and metal compounds have been used in The importance of metal compounds in medicine is medicine for several thousands of years. In this review we undisputed, as can be judged by the use of compounds of summarized the anti-cancer activities of the ten most active antimony (anti-protozoal), bismuth (anti-ulcer), gold (anti- metals: arsenic, antimony, bismuth, gold, vanadium, iron, arthritic), iron (anti-malarial), silver (anti-microbial) and rhodium, titanium, gallium and platinum. The first reviewed platinum (anti-cancer) in the treatment of various diseases. metal, arsenic, presents the anomaly of displaying anti-cancer In terms of anti-tumour activity, a wide range of compounds and oncogenic properties simultaneously. Some antimony of both transition metals and main group elements have derivatives, such as Sb2O3, salt (tartrate) and organic been investigated for efficacy (1). The earliest reports on the compounds, show interesting results. Bismuth directly affects therapeutic use of metals or metal-containing compounds in Helicobacter pylori and gastric lymphoma; the effects of cancer and leukemia date from the sixteenth century. bismuth complexes of 6-mercaptopurine are promising. Superoxide dismutase inhibition leads to selective killing Gold(I) and (III) compounds show anti-tumour activities, of cancer cells in vitro and in vivo (2,3). As a consequence, although toxicity remains high. Research into the potential use reactive oxygen species (ROS) may not only be involved in of gold derivatives is still ongoing. Several derivatives of causing cancer, but could also be a specific treatment of vanadium show anti-proliferative activity, but their toxicity tumours. must be overcome. Several pieces of evidence indicate that iron deprivation could be an excellent therapeutic approach; Arsenic furthermore, it is synergistic with classic anti-cancer drugs. Rhodium belongs to the same group as platinum and it also Arsenic compounds are natural substances used in China presents interesting activity, but with the same nephrotoxicity. for medical treatment for more than twenty-five centuries. Several rhodium compounds have entered phase I clinical Arsenic trioxide (As2O3) has been used for ten years in trials. In contrast to the platinum complexes, titanium patients with acute promyelocytic leukemia (APL). It is derivatives showed no evidence of nephrotoxicity or apparent that arsenic trioxide is a successful treatment for myelotoxicity ; titanocene dichloride is undergoing clinical trial. APL. Furthermore, arsenic trioxide is safe and effective not The anti-proliferative effect of gallium could be related to its only in patients with leukemia, but also in patients with competition with the iron atom; in addition a derivative many other malignancies (4). appears to reverse the multidrug resistance. The last metal At the present, there are several possible explanations for reviewed, platinum, has given some of the very best anti-cancer the mechanism of action of arsenic trioxide. It induces a drugs. Four derivatives are used today in the clinic; their p53-dependent G1 or G2/M cell cycle arrest, through an mechanism of action and of resistance are described. activation of caspase 8 or caspase 9 (5). Others have also reported that arsenic trioxide induces cell cycle arrest or apoptosis (6). In the study of Li et al., it induces apoptosis and differentiation in cancer cells (7), and the latter can be Correspondence to: B. Desoize, Laboratoire de Biochimie et de blocked by cAMP analogs (8). Biologie Moléculaire, Faculté de Pharmacie, 51 rue Cognacq-Jay, The anti-carcinogenic effects of arsenic trioxide may be 51096 Reims cedex, France. Tel: 06.76.87.45.62, Fax: 03.26.91.37.30, related to the induction of apoptosis (9). The up-regulation e-mail: [email protected] of p53 and down-regulation of bcl-2 may be an underlying Key Words: Anti-cancer drugs, arsenic, antimony, bismuth, gold, mechanism (10). A simultaneous down-regulation of bcl-2 vanadium, iron, rhodium, titanium, gallium, platinum, review. and up-regulation of bax was also reported by Zhao et al. 0250-7005/2004 $2.00+.40 1529 ANTICANCER RESEARCH 24: 1529-1544 (2004) (11). However, it should be noted that, although a high The regimen of daily intravenous administration for 4-8 concentration of arsenic trioxide (5 Ìmol/l) causes weeks has its attendant drawbacks: inconvenience, risks and apoptosis, at low concentrations (0.5 Ìmol/l) it causes cell expense of maintaining suitable vascular access and proliferation (9,12). hospitalization. Sturlan et al., therefore, developed an oral The induction of apoptosis could be also related to an formulation and determined the systemic bioavailability of increase in the production of ROS and a decrease in anti- arsenic in patients. Compared with i.v. dosing, the oral arsenic oxidation capacity (9). As a matter of fact, toxic lipid trioxide solution was more convenient and cost effective, with peroxidation products, such as the polyunsaturated fatty a similar systemic bioavailability of arsenic (24). acid docosahexaenoic acid (DHA), sensitize tumor cells to ROS-inducing anti-cancer agents (13). Arsenic trioxide Antimony induces an increase in GSH content as a response to oxidative stress (14). This mechanism of action provides a We have seen that As2O3 has remarkable potential against biochemical basis for developing new drug combination promyelocytic leukaemia and, because of structural analogy, strategies, using arsenic trioxide to enhance the activity of Sb2O3 has also been tested on the same leukemia with anti-cancer agents by promoting the generation of free interesting results (25). Although normally regarded as a radicals (2). poison, Sb2O3 is less toxic than As2O3. Histone H3 phosphoacetylation associated with the The most studied antimony(III) compounds are Caspase-10 gene may play an important role in the organometallic. A series of antimony(III) compounds with induction of apoptosis (15). polydentate carboxylic acids have shown anti-tumour activity According to Duyndam et al., p38 mediates the induction in mice inoculated with S180 solid tumours (26). of VEGF mRNA expression by sodium arsenite (12). On Four diphenylantimony(III) thiolates have been tested. the other hand, the p38 MAP kinase pathway could be a Three of them had marginal activity (ratio of Tumour to negative regulator of the apoptosis and inhibition of Control, T/C < 125 %). A fourth compound was the most malignant cell growth induced by arsenic trioxide (16,17) active, but increased doses were associated with increased Unfortunately, resistance to arsenic trioxide has been toxicity, including potential mutagenicity (27). reported. It is accompanied by cross-resistance to Triphenylantimony(V) polyamines displayed some ionidamine and oxaliplatin (18). This resistance does not cytotoxicity against several cell lines. Triorganoantimony(V) appear to be related to the expression of P-glycoprotein disalicylates showed no significant activity and were not (19). It has been reported that resistance to arsenic trioxide investigated further (28). in primitive UCB (primary umbilical cord blood) CD34+ The anti-tumour activity of potassium antimony tartrate cells is most probably related to cell-cycle status (19). in lymphoid malignancies is interesting (29-30), but it is Several cell lines are sensitive to arsenic trioxide: compromised by cross-resistance with cisplatin in human esophageal carcinoma cells (9), OVCAR-3 (12), renal cell ovarian carcinoma and other cell lines (31). Also, exposure carcinoma cells (6) and small cell lung cancer (NeI-H cells) to potassium antimony tartrate has been associated with (10). Arsenic trioxide has also been shown to be active over-expression of the multi-drug resistance-associated against nasopharyngeal carcinoma xenografts in BALB/C protein (MRP1), a drug export pump (32). nude (20,21). Disappointingly, arsenic trioxide causes cardiotoxicity, with Bismuth electrocardiographic abnormalities (22). Furthermore, it induces hyperleukocytosis and APL differentiation syndrome Helicobacter pylori is implicated in the causation of gastric (21). These effects can be prevented or managed successfully lymphoma and treatment with bismuth results in regression with careful patient monitoring during treatment. of the disease or even a cure (33). Bismuth increases Interestingly, trisenox, the injectable formulation of production of metallothionein, a property which may be arsenic trioxide, has no known cross-resistance with ATRA used to reduce the toxic side-effects of cisplatin (34). or other anticancer agents. In addition, trisenox does not Bismuth complexes of 6-mercaptopurine were the first anti- cause hair loss and is not myelosuppressive in patients with tumour compounds tested. They yielded promising results, as acute promyelocytic leukemia (21). compared to platinum(II) analogues. Organobismuth There is promising evidence of the activity of arsenic compounds were also tested, but no useful activity was trioxide plus ascorbic acid in refractory/relapsed myeloma. observed (28). The mechanism of potentiation by ascorbic acid is due to The emission of ·-particle by bismuth compounds shows intracellular glutathione depletion. This treatment has potential in the form of radio-therapeutic