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Characterization of the Interaction of Cryptophycin 1 (CANCER RESEARCH 56. 4398-4406. October 1. 1996] Characterization of the Interaction of Cryptophycin 1 with Tubulin: Binding in the Vinca Domain, Competitive Inhibition of Dolastatin 10 Binding, and an Unusual Aggregation Reaction Ruoli Bai, Robert E. Schwartz, John A. Kepler, George R. Pettit, and Ernest Hamel1 Laboratory of Molecular Plitinmict)lt>xy. Division of Basic Sciences, National Cancer Institute, NIH, Bethcsila, Marciatiti 20XV2 ¡K.H., E. H.l; Merck, Sharp unti Dohnie Research Laboratories. Railway, New Jersey 07065 [R. E. S.¡; Research Triangle Institute. Research Triangle Park, North Carolina 27709 ¡J.A. K.]; ami Cancer Research Institute ami Department of Chemistry, Arizona State University, Tempe, Arì-onaR52H7 [G. R. P.I ABSTRACT activity against a number of solid tumors implanted in mice, and CP1 or a closely related agent will probably be evaluated as an experi The ¡mi¡miloticdepsipeptide cryptophycin l (CP1) was compared to mental antineoplastic agent in clinical trials. the antimitotic peptide dolastatin 10 (DIO) as an antiproliferative agent We have been studying interactions of antimitotic peptides (DIO and in its interactions with purified tubulin. The potent activity of CP1 as and analogues; Refs. 9-14) and depsipeptides (DIS and analogues; an inhibitor of cell growth was confirmed. The agent had an IC50 of 20 p.vt against L1210 murine leukemia cells versus 0.5 n.Mfor DIO. Both drugs Ref. \5f with purified tubulin, as well as the comparative antiprolif were comparable as inhibitors of the glutamate-induced assembly of erative activities of these agents (structures in Fig. 1). DIO binds in a purified tubulin, with DIO being slightly more potent. CP1, like DIO, was distinct region of the tubulin a-ß-heterodimer, since it noncompeti- a noncompetitive inhibitor of the binding of [3H]vinblastine to tubulin tively inhibits the binding of radiolabeled Vinca alkaloids to tubulin, (apparent K„3.9/IMI; and the depsipeptide was a competitive inhibitor of as do an unrelated group of sponge-derived macrocyclic polyethers the binding of |'H]D10 to tubulin (apparent K,, 2.1 JUM).CP1 was less termed halichondrins (16) and spongistatins (17, 18). The binding of potent than DIO as an inhibitor of nucleotide exchange on tubulin, but the |'H]D10 to tubulin was inhibited competitively by one of its ana two drugs were equivalent in stabilizing the colchicine binding activity of logues [(19a/?)-isodolastatin 10] and by another peptide antimitotic tubulin. CP1, like DIO, caused the formation of extensive structured agent, phomopsin A, and noncompetitively by spongistatin 1 (18). aggregates of tubulin when present in stoichiometric amounts relative to With [3H]D10, we observed tenacious, but reversible, binding to the protein. Whereas at lower concentrations the drugs were equivalent in causing formation of small oligomers detected by gel permeation high- tubulin, and formation of drug-containing tubulin oligomers and performance liquid chromatography, there were notable differences in the coiled polymers that could be studied by HPLC, electron microscopy, aggregation reactions induced by the two drugs. The electron micro- or turbidity development (13, 18). DIO, moreover, potently inhibited graphic appearance of the DIO-induced aggregate differed substantially nucleotide exchange on tubulin, although it did not displace nucleo from that of the CPl-induced aggregate. With DIO, but not CP1, aggre tide bound in the exchangeable site. The peptide prevented time- gate morphology was greatly altered in the presence of microtubule- dependent decay of CLC binding activity of tubulin (10). associated proteins. Finally, although CP1 caused the formation of mas In contrast, the depsipeptide D15. despite its partial structural sive aggregates, as did DIO, there was little turbidity change with the analogy to DIO and its ability to inhibit tubulin polymerization, depsipeptide as opposed to the peptide. neither induces tubulin oligomerization nor affects the interactions of other ligands with tubulin (13, 15). Since we have not succeeded in INTRODUCTION demonstrating an interaction of |3H)D15 with tubulin,4 we have attributed this difference in properties to much weaker binding of D15 Antimitotic natural products have a long history of use as poisons and as therapeutic agents. Ever since CLC2 was used to isolate tubulin to tubulin. Our work with the dolastatins made us particularly curious about (1), the target protein for this class of drug, there has been a continu CP1. We wondered how its properties would compare with those of ing discovery of new agents remarkable for their chemical diversity the dolastatins. particularly whether its being a depsipeptide indi and often for their potent cytotoxicity (2). Smith el al. (3) reported that the depsipeptide CP1 (previously known as "cryptophycin" and cated a relatively weak interaction with tubulin. We found, how "cryptophycin A"; structure in Fig. 1, as reported by Barrow et al. in ever, that CP1 resembled DIO more than D15 in its effects on tubulin. The agent noncompetitively inhibited [ 'H|VLB binding to Ref. 4). a compound initially isolated as a potent antifungal agent tubulin and competitively inhibited |'H]D1() binding to tubulin. from the terrestrial cyanobacterium Nostoc sp. (5), caused cells to Like DIO, CPI caused formation of structurally distinct tubulin accumulate in mitosis with the disappearance of intracellular micro- aggregates, but this occurred without a change in the turbidity of tubules. IC50s as low as 2 pM were obtained for cell growth, and these the tubulin solution. CPI induced-aggregates differed morpholog values for CP1 were approximately 100-1000-fold lower than those ically from those induced by VLB and DIO under the same reaction obtained with paclitaxel (Taxol), CLC, and VLB. Moreover, CP1 was conditions. In addition, we confirmed the potent antimitotic activ a poor substrate for the multidrug resistance transport protein. ity reported by Smith et al. (3). Kerksiek el al. (6) and Smith and Zhang (7) subsequently found that CP1 inhibited tubulin assembly and the binding of VLB but not CLC to tubulin. Golakoti et al. (8) found that CP1 had excellent In vivo MATERIALS AND METHODS Materials. CPI was purified from the culture medium used to grow the Received 4/8/96; accepted 7/30/96. Nostoc sp. (5). Synthetic DIO (19). |'H]D10 ( 13), synthetic D15 (20). ( 19aA)- The costs of publication of this article were defrayed in part by Ihe payment of page charges. This article must therefore be hereby marked advertisement in accordance with isodolastatin 10 (21), an isomer of DIO with reversal of configuration at 18 U.S.C. Section 1734 solely to indicate this fact. position C-19a, and electrophorelically homogeneous bovine brain tubulin and 1To whom requests for reprints should be addressed, at Laboratory of Molecular heat-treated MAPs (22) were prepared as described previously. [8-uC|GTP. Pharmacology. Division of Basic Sciences. National Cancer Institute. NIH, Building 37. Room 5C25, Bcthesda. MD 20892. Phone: <301) 496-4855; Fax: (301) 496-5839. - The abbreviations used are; CLC. colchicine; VLB. vinblastine; CP1. cryptophycin 1; 'G. R. Petlit, E. J. Flahive, M. R. Boyd. R. Bai. E. Hamel. and J. M. Schmidt, DIO. dolastatin 10; D15. dolastatin 15; HPLC. high-performance liquid chromatography: submitted for publication. MAPs. microlubule-associated proteins; MES. 4-morpholineethanesulfonate. 4 R. Bai. J. T. Mullaney. G. R. Pettil. and t. Hamel. unpublished observations. 439S Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1996 American Association for Cancer Research. IMIK\( IION Oh CRYPTOPHYCIN 1 WITH TI Hll IN OCH, CRYPTOPHYCIN 1 Fig. 1. Structural formulas fur CPI. DIO. and D15. 11 I m ì\ S ^^ I O CH OCH O / X —¿N DOLASTATIN 10 H3C CH3H3C««« CH3H3C CH3 CH, DOLASTATIN 15 |'H|VLB. and |'H|CLC were obtained from Moruvek Biochemicals. Amer- Tubulin aggregation5 was followed by HPLC on a 7.5 x 300-mm TSK shum. and DuPont. respectively. Maytansine and rhizoxin were obtained from G3000SW gel permeation column with an LKB system in line with a Ramona the Drug Synthesis and Chemistry Branch, National Cancer Institute; CLC and 5-LS flow detector. The column was equilibrated with a solution containing VLB were from Sigma Chemical Co. All drugs were dissolved in DMSO. and 0.1 M MES (pH 6.9) and 0.5 IHMMgCK. Absorbance data were evaluated with equivalent amounts of solvent were added to control reaction mixtures. MES Raytest software on an IBM-compatible computer. Tubulin aggregation was was prepared as 1.0 Mstock solutions, adjusted to the indicated pH values with also followed turbidimetrically at 350 nm in Gilford spectrophotometers. NaOH: monosodium glutamate was prepared as a 2.0 M stock solution, Negatively stained specimens were examined in a Zeiss model IOCA adjusted to pH 6.6 with HCI. electron microscope. About 5 ¿tlwere placed on a 200-mesh. carbon-coated. Methods. Inhibition of glutamate-induced assembly of purified tubulin Formavar-treated copper grid, and after 5-10 s. were washed off with 5-10 was evaluated in 0.25-ml reaction mixtures following a drug-tubulin pre- drops of 0.5% uranyl acetate. Excess stain was removed by absorbance into incubation for 15 min at 37°Cwithout GTP in 0.24 ml. Final concentrations torn filter paper. were 1.0 mg/ml (10 \M) tubulin, 1.0 M monosodium glutamate, 1.0 niM Drug effects on the growth of L1210 murine leukemia cells were deter MgCK. 0.4 mM GTP, and 47c (v/v) DMSO. Assembly was initiated by a mined on cells grown under 5% CO, in 5 ml of RPMI 1640 supplemented with 75-s jump from 0 to 37°Cand was monitored in Gilford spectrophotometers 17% fetal bovine serum. 2 HIMglutamine. and 10 /j.g/ml gentamicin sulfate. at 350 nm. The extent ot the reaction was evaluated after 20 min. In studies Cell number was determined with a Coulter Counter following a 24-h incu nl inhibition of assembly with MAPs, there was no drug-tubulin preincu- bation at 37°C.Mitotic index was evaluated by microscopic examination of bation.
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