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In Situ Allicin Generation Using Targeted Alliinase Delivery

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In Situ Allicin Generation Using Targeted Alliinase Delivery Molecular Cancer Therapeutics 1295 Inhibition of tumor growth by a novel approach: In situ allicin generation using targeted alliinase delivery Talia Miron, Marina Mironchik, David Mirelman, odorless precursor alliin (S-allyl-L-cysteine sulfoxide). Meir Wilchek, and Aharon Rabinkov Alliin is converted to allicin, pyruvate, and ammonia by the pyridoxal 5V-phosphate (PLP)-dependent enzyme allii- Department of Biological Chemistry, The Weizmann Institute of Science, nase (alliin lyase; EC 4.4.1.4) (3), which is enclosed in Rehovot, Israel compartments within the garlic clove cells (Scheme 1). Crushing the clove exposes alliin to the enzyme, to initiate the following reaction: Abstract Allicin (diallyl thiosulfinate), a highly active component in extracts of freshly crushed garlic, is the interaction product of non-protein amino acid alliin (S-allyl-L-cysteine sulfoxide) with the enzyme alliinase (alliin lyase; EC Allicin reacts rapidly with free thiol groups and 4.4.1.4). Allicin was shown to be toxic in various penetrates biological membranes with ease (4, 5). It mammalian cells in a dose-dependent manner in vitro. therefore disappears from the circulation within a few We made use of this cytotoxicity to develop a novel minutes after injection (2, 4–6). This explains why the approach to cancer treatment, based on site-directed versatile and valuable activities of allicin, including its generation of allicin. Alliinase from garlic was chemically potent antibiotic and cytotoxic effects, were demonstrated conjugated to a mAb directed against a specific tumor thus far only in vitro (2, 7–9). We present here a new marker, ErbB2. After the mAb-alliinase conjugate was approach to anticancer therapy based on a localized, site- bound to target tumor cells, the substrate, alliin, was directed production of allicin. This approach can also be added. In the presence of alliin, tumor-localized alliinase used to develop a wide range of antibiotic treatments. produced allicin, which effectively killed N87 and CB2, Alliinase is first targeted to the tumor. Conjugating the both ErbB2-expressing cells in vitro, whereas 32D cells (a enzyme to a carrier, in this case, a mAb specific to a tumor- murine hematopoietic progenitor cell line, devoid of the associated surface antigen, enables the targeting process. ErbB2 receptors) were not affected. Moreover, using N87, Alliin is then administrated into the circulation, which a human tumor cell line xenograft in athymic nude mice, results in the formation of allicin only at the site of alliinase we demonstrated for the first time, a high antitumor localization. The strategy for drug delivery based on activity of allicin that was produced in situ by the antibody-directed enzyme prodrug therapy (ADEPT) was conjugate, on alliin administration in vivo, while at the previously described (10–14). As in the ADEPT system, so same time other tissues were unharmed due to the inert alliinase-directed therapy uses mAbs specific to tumor cell nature of alliin and the high clearance rate of allicin. The antigens, to anchor the enzyme onto the cell surface. The effect of the treatment on tumor growth arrest became second step, however, consists of the administration of significant 2 weeks after its onset, and it continued to rise, alliin, a naturally occurring, inert non-protein amino acid reaching highly significant inhibition a week later. Ten that is converted to the cytotoxic allicin only on interaction days after the end of the treatment (day 18), tumor with the enzyme, anchored on the tumor cell surface. The growth inhibition was still the same. (Mol Cancer Ther. system presented here mimics the natural situation in 2003;2(12):1295–1301) crushed garlic cloves, where allicin formation occurs only after alliin becomes accessible to the enzyme. The advantages of this approach over the conventional ADEPT are the following: allicin and its precursor alliin Introduction which is nontoxic (unlike other drugs) are natural food Allicin (diallyl thiosulfinate) is the best known biologically constituents. Allicin acts swiftly as a powerful anticancer active component in the extract of freshly crushed garlic (1, agent and it has an extremely short lifetime. Addition- 2). Intact garlic cloves do not contain allicin, but only its ally, its secondary products such as allylmercaptogluta- thione and allylmercaptocysteine were shown to bear beneficial antioxidant characteristics (4). Thus, a compre- Received 8/5/03; revised 9/18/03; accepted 10/1/03. hensive expression of the potent biological activity of The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby allicin is achieved. marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Materials and Methods Grant support: Levine Center and Yeda Co. at the Weizmann Institute of Science. Materials Requests for Reprints: Aharon Rabinkov, Department of Biological 3-(2-Pyridyldithio) propionic acid N-hydroxysuccinimide Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972-8-9344340; Fax: 972-8-9468256. ester (SPDP), DTT, and PLP were purchased from Sigma E-mail: [email protected] (St. Louis, MO). Alliin was synthesized according to Downloaded from mct.aacrjournals.org on September 27, 2021. © 2003 American Association for Cancer Research. 1296 In Situ Allicin Production Inhibits Tumor Growth in Mice Ref. (15). Allicin was prepared by applying synthetic alliin (pH 6.5), containing 10% glycerol]. The protein was collected onto an immobilized alliinase column (16). Allicin concen- and concentrated by Centriprep-30 (Amicon, Beverly, MA) tration was determined as described in Ref. (17). 2-Nitro- at 4jC. The degree of SPDP-alliinase modification was 1–1.4 5-thiobenzoate (NTB) was synthesized according to Ref. (18). residues SPDP/E. The modified protein was stored in 50% [Methyl-3H]thymidine was purchased from Amersham glycerol at À20jC. SPDP modification of mAb: The only Pharmacia Biotech (Amersham, United Kingdom). difference from the procedure described above for alliinase Biochemical Analysis was a 20-M excess of SPDP over the mAb. The degree of Protein concentration was measured at 280 nm, using SPDP-mAb modification was 3–4 SPDP residues/mAb, and À1 À1 0.1% the modified mAb was stored in PBS at 4jC. E280 = 77.000 M cm (E280 = 1.54) for alliinase and À1 À1 0.1% 210.000 M cm for purified mAb (E280 = 1.4). The Preparation of the mAb-Alliinase Conjugate number of SPDP residues on the modified proteins was SPDP-mAb was reduced with DTT (5 mM, 10–20 min). determined according to Ref. (19). Purification of alliinase DTT was removed by gel filtration. Protein-containing was done according to Refs. (20, 21). Quantitative assess- fractions (mAb-SH) were collected and immediately com- ment of alliin and allicin was performed by high- bined with SPDP-alliinase, at a molar ratio of SPDP- performance liquid chromatography (17). Determination alliinase/mAb-SH (1.1/1). The conjugation mixture was of alliin content in the serum was done after i.p. injection of incubated 1 h at 24jC with 20% sucrose, adjusted to 50% alliin (0.2 ml of 30 mg/ml) to mice. Serum aliquots (25 Al) glycerol, and stored at À20jC. Before any further treatment, were treated with 90% methanol and proteins precipitated the conjugated alliinase was freed from sucrose and overnight at À20jC. After centrifugation, the supernatants glycerol by gel filtration. Further purification of conjugated were lyophilized. The dry material was dissolved in water proteins from non-conjugated was done by size-exclusion and was assayed for alliin according to Ref. (22). chromatography on Superdex G200 (1.6 Â 60; Pharmacia) Enzymatic Activity with 50 mM phosphate buffer (pH 6.5), containing 10% Alliinase activity was determined by the NTB method in a glycerol and 2 mM PLP. cell free system according to Ref. (17). An ELISA system Radiolabeling of Proteins using 96-well plates was developed to assay the activity of Iodination of alliinase, free mAb, and conjugates was the enzyme conjugates. Wells were coated with either done with 125I, using the Chloramine-T method (0.5 mCi protein A (5 Ag/ml), or with paraformaldehyde-fixed N87 Na125I/100 Ag protein) according to Ref. (26). The specific or CB2 cells, at a sub-confluent culture density. Fixation was radioactivity of 125I-alliinase, 125I-mAb, and 125I-mAb- done with paraformaldehyde (3%) in PBS for 30 min, alliinase was 0.51, 2.26, and 0.85 ACi/Agprotein, followed by washing (3Â) with PBS. Binding of mAb- respectively. alliinase conjugates to the antigen was done at 24jC for Cell Lines and Tissue Culture 1–2 h in the presence of 2 mM PLP. After removal of N87, a human gastric adenocarcinoma cell line, express- unbound protein by washing (3Â) with PBS containing ing the ErbB2 receptors (27), HeLa HtTA-1 (28), BHK, baby 0.05% Tween 20, the activity of adsorbed conjugated hamster kidney cells, and NIH 3T3 cells were grown in À4 alliinase was determined by using NTB (3 Â 10 M) and DMEM supplemented with antibiotics and 10% heat- À3 alliin (0.6 Â 10 M)in50mM phosphate buffer (pH 7.2) inactivated FCS; CB2, a Chinese hamster ovary (CHO) cell containing 2 mM EDTA (0.1 ml/well). The decrease in line transfected with mammalian expression vector ErbB2 A412 nm was recorded after 30 min. Wells, to which no (29), was grown in DMEM/F12 (1:1) medium supple- enzyme was added, served as controls (17). One unit of mented with antibiotics and 10% heat-inactivated bovine activity was defined as the amount of enzyme required to calf serum; 32D, a murine hematopoietic progenitor cell produce 1 Amol of pyruvate per minute. line (30), devoid of the ErbB2 receptors, was grown in Antibodies suspension in RMPI 1640 supplemented with glutamine, N28 (IgG1) mAb, anti-ErbB2 (23, 24), was purified from antibiotics, IL-3, and 10% FCS (31).
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