Perspectives of Antimony Compounds in Oncology
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Acta Pharmacol Sin 2008 Aug; 29 (8): 881–890 Invited review Perspectives of antimony compounds in oncology Pankaj SHARMA1,3, Diego PEREZ1, Armando CABRERA1, Noe ROSAS1, Jose Luis ARIAS2 1Instituto De Química, UNAM Circuito Exterior, Coyoacan México DF.04510; 2Facultad de Estudios Superiores Cuautitlán, UNAM, Cuautitlan Izcalli, Estado de México 54700, Mexico Key words Abstract antimony; organoantimony; antitumoral; Antimony, a natural element that has been used as a drug for over more than 100 leishminiatic drugs years, has remarkable therapeutic efficacy in patients with acute promyelocytic 3Correspondence to Dr Pankaj SHARMA. leukemia. This review focuses on recent advances in developing antimony anti- Phn 52-55-5622-4556. cancer agents with an emphasis on antimony coordination complexes, Sb (III) and E-mail [email protected] Sb (V). These complexes, which include many organometallic complexes, may Received 2008-03-10 provide a broader spectrum of antitumoral activity. They were compared with Accepted 2008-04-28 classical platinum anticancer drugs. The review covers the literature data pub- lished up to 2007. A number of antimonials with different antitumoral activities are doi: 10.1111/j.1745-7254.2008.00818.x known and have diverse applications, even though little research has been done on their possibilities. It might be feasible to develop more specific and effective inhibitors for phosphatase-targeted, anticancer therapeutics through the screen- ing of sodium stibogluconate (SSG) and potassium antimonyltartrate-related compounds, which are comprised of antimony conjugated to different organic moieties. For example, SSG appears to be a better inhibitor than suramin which is a compound known for its antineoplastic activity against several types of cancers. Introduction macological properties and a wide range of antitumoral Antimony, a neutral substance that has been used as a activities. Strategies for developing new anticancer agents drug for over 100 years, has remarkable therapeutic efficacy include the incorporation of carrier groups that can target in patients with acute promyelocytic leukemia (APL). It tumor cells with high specificity. In an attempt to beat the exerts apoptosis in dose- and time-dependent manner. Ad- resistance pathways that have evolved to eliminate the drug, vances in biocoordination chemistry are crucial for improv- developing new complexes that bind to DNA in a fundamen- ing the design of compounds to reduce toxic side-effects tally different manner than cisplatin is also of interest. It has and to understand their mechanisms of action. A great num- been widely accepted that the organic ligands associated ber of metallic complexes display a pronounced antitumoral with the metal atom in these complexes play an important activity, which makes them of a high interest for applications role during their transport and assimilation at the membrane in the treatment of different types of cancer[1]. This research level and inside the cell. began in 1969 with the discovery of cisplatin by Rosenberg To date, practically all transition and main group metals et al[2] in the treatment of testicle and ovary cancers, despite have been tested for antitumoral properties, and interestingly, the fact that metal (oid)-containing compounds have been a number of them have been shown marginal to good activ- used historically as medicines for several thousands of years, ity towards standard animal tumors[4-9]. Within the main especially in Chinese and Indian traditional medicine. group metal, inorganic and organometallic complexes of The clinical success of cisplatin and other platinum com- gallium, germanium[10,11], and tin have been the focus of most plexes is limited by the significant side-effects or intrinsic antitumoral studies. Gielen et al recently published antitu- resistance[3]. Therefore, much attention has focused on de- moral studies of a series of germanium rings against differ- signing new coordination compounds with improved phar- ent human cancer cell lines. ID50 (Infectous dose 50) values ©2008 CPS and SIMM 881 Sharma P et al Acta Pharmacologica Sinica ISSN 1671-4083 of most of the compounds were comparable with clinically Nitrogen mustard cyclophosphamide (Figure 2) is an alky- employed drugs doxorubicin and cisplatin[12]. The same lating agent reported to possess significant antitumoral ac- group has patented tin carboxylate complexes for their anti- tivity in selected malignant neoplasms; however, its 1:1 ad- [13,14] tumoral properties that were later renewed . Recently, duct with SbCl3L presented no activity against L1210 leuke- chemical and biotechnological developments in organotin mia and Ehrlich ascites tumor, similar to the inactivity of cancer chemotherapy emphasizing the coordinating ability other metal coordination compounds[29]. of organotin compounds towards DNA and the action mode A series of antimony (III) complexes along with other of organotins in cancer chemotherapy was reviewed[15]. In metal ion complexes, that is, Co, Ni, Sn, and Pb with different contrast, antimony compounds[16-17] appear to have not been polydentate carboxylic acids have also been investigated as well documented as other metal-containing species, de- for their antitumoral action. Preliminary results have indi- spite the fact that organoantimonials have been used suc- cated that the uncoordinated ligands as such are not as po- cessfully for more than half a century in the treatment of tent as antimony complexes with these ligands, showing the leishmaniases[18-21]. Leishmaniases are ineffective parasitic presence of Sb (III) for activity. Of the other metal ions diseases that are injected into mammals via sand flies, which investigated with these ligands, only the antimony (III) spe- are endemic in 88 countries, and mainly affect developing cies have shown activity[30,31]. countries. Pentavalent antimonials, including antimony bis- The cytotoxicity of NH4(Sb[Hdtpa]) was examined in hu- (4,5-dihydroxybenzene-3,5-disulphonate) Stibophen man promyelocytic leukemia (HL-60) cells. Complexes at 1, (Scientific coorp. USA), antimony (III) gluconate (Triostam; 10, and 100 µg/mL showed 18%, 70%, and 100% cell inhibi- Canton Chem, USA), meglumine antimoniate (Glucantime; tion within 24 h, respectively. The antitumoral activity of Aventis, France), and sodium stibogluconate (SSG; NH4(Sb[Hdtpa]) (Figure 3) (30 mg/kg) towards solid experi- Pentostam; GlaxoSmithKline, US and UK) have been used mental animal tumors (S180) in mice reduced the weight of for a long time as antileishmanial drugs. In spite of several the tumors to 74% of that of the control values on d 9 after limitations, including side-effects, need for daily parentral tumor transplantation[30]. administration, and drug resistance, antimonials are still first- In vitro antitumoral activity of antimony (III) nitrilotriacetate line drugs (Figure 1). The metabolism and mechanisms of complexes ( nitriloacetate compound shown in Figure 4) action are still being investigated. It is not clear whether against Ehrlich adenocarcinoma (EAC) in mice was studied. the final active form of pentavalent antimonials is Sb (V) Compound (NH4)2Sb(Nta)( HNta)-nH2O (I) and Na2Sb(Nta) or Sb (III), although recent studies suggest that pentavalent (HNta)×2H2O (II) produced a significant (60%–90%) increase antimony acts as a prodrug that is converted to active and in the survival rate of test mice with ascetic EAC, at an opti- more toxic trivalent antimony, and thiols may act as a re- mum therapeutic dose of 25–50 mg/kg in the absence of sig- ducing agent in this conversion[22]. Some reports have sug- nificant toxicity in this dose range. The results showed good gested the intrinsic antileishmanial activity of Sb (V), which prospects in the search for new antitumoral agents among forms a complex with adenine ribonucleoside. Sb–ribo- Sb(III) complexes with aminopolycarboxy ligands[32]. nucleoside complexes may act as inhibitor of leishmania Similarly, antimony (s-benzyldithiocarbazate) complexes purine transporters or penetrate inside the parasite and then display antitumoral agents against melanoma (skin cancer interfere with the purine nucleoside metabolism[23]. cells)[33]. During the last decade, there has been progress made The toxicity of a novel water stable antimony (III) com- towards the improvement of antimonial chemotherapy for plex with heterocyclic thioamide, 2-mercaptopyrimidine leishmaniases, but the application of antimonials as antitu- (pmtH) (Figure 5) of formula Sb(pmt)3]0.5(CH3OH), against moral agents needs attention. tumor pleiomorphic cells was studied. Pleiomorphic cells were isolated from a leiomyosarcoma tumor in the Wistar rat Trivalent antimony compounds (chemical carcinogenesis using 3,4-benzopyrene BaP). The result showed that the compound did not destroy or prevent In the mid 1960s, Hsu et al[24–26] reported the antitumoral multiplication in vitro leiomyosarcoma cells at low doses. activity of inorganic compounds of antimony and demon- The antimetastatic capability study showed that the com- strated that some Sb(III) with aminopolycarboxy ligands pound had shown inhibition of cancer cell-induced aggrega- increased the life span of mice bearing the Ehrlich ascites tion up to the value of 10% in all mmol/L concentrations tumor and spindle sarcoma. It was later reported that some tested[34]. tungstoantimonates with complicated compositions exhib- Recently, new antimony (III) complexes with the hetero- ited antitumoral activity[27,28]. 882 Http://www.chinaphar.com