New Tumor Promoters from Marine Natural Products - American

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Chapter 18

New Tumor Promoters from Marine Natural Products 1

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Hirota Fujiki , Masami Suganuma , Hiroko Suguri , Shigeru Yoshizawa , Kanji Takagi , Michie Nakayasu , Makoto Ojika , Kiyoyuki Yamada , Takeshi Yasumoto , Richard E. Moore , and Takashi Sugimura 1

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Cancer Prevention Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan Common Laboratory, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan Faculty of Science, Nagoya University, Nagoya 464, Japan 4Department of Food Chemistry, Faculty of Agriculture, Tohoku University, Tsutsumidori Amamiya, Sendai 980, Japan 5Department of Chemistry, University of Hawaii, Honolulu, HI 96822 National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan 2

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T u m o r promoters induce t u m o r formation from initiated cells. W e have found new tumor promoters that are structurally different from 12-O-tetradecanoylphorbol-13-acetate ( T P A ) . These new t u m o r promoters include lyngbyatoxin A debromoaplysiatoxin, aplysiatoxin, bromoaplysiatoxin, oscillatoxin A and anhydrodebromoaplysiatoxin isolated from marine blue-green algae, and dibromoaplysiatoxin synthesized chemically; palytoxin isolated from a marine coelenterate; and okadaic acid isolated from a black sponge. These new t u m o r promoters are classified as T P A - t y p e and n o n - T P A type tumor promoters o n the basis o f their abilities to bind to the p h o r b o l ester receptor. Lyngbyatoxin A and aplysiatoxins belong to the T P A - t y p e , and palytoxin and okadaic acid are n o n - T P A type t u m o r promoters. TPA-type t u m o r promoters activate protein kinase C , which serves as the phorbol ester receptor, while n o n - T P A type t u m o r promoters do not activate protein kinase C i n vitro. Therefore, these two types o f t u m o r promoters provide direct evidence for divergent mechanisms o f action i n two-stage carcinogenesis experiments o n mouse skin. T h e process o f chemical carcinogenesis consists o f two stages, initiation and p r o m o t i o n ( i ) . Initiation is caused by a single application o f a small amount o f a carcinogen, which induces irreversible genetic damage to D N A A p p l i c a t i o n o f the carcinogen, 7,12-dimethylbenz(a)anthracene ( D M B A ) , for example, to the skin o f the back o f a mouse was reported to induce mutation o f an oncogene, so-called activat i o n o f the ras gene (2). Agents that then p r o m o t e carcinogenesis from initiated cells are called tumor promoters (5). Treatment with D M B A followed by repeated applications o f a t u m o r promoter, results i n a high percentage o f tumor-bearing mice, whereas treatment with an initiator alone o r t u m o r promoter alone does not produce any tumors i n mouse skin. T P A o r phorbol-myristate-acetate ( P M A ) is

0097-6156/90/0418-0232$06.00/0 o 1990 American Chemical Society

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New Tumor Promoters from Marine Natural Products 233

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the classical t u m o r promoter, isolated from croton o i l , the o i l o f seeds o f Croton tiglium L , belonging to the Euphorbiaceae (4,5) (Figure 1). W e have so far found 20 so-called new t u m o r promoters, because they are structurally different from p h o r b o l esters (6). Naturally occurring t u m o r promoters can be classified according to their sources: Actinomycetes, terrestrial plants, and marine organisms (Table I) (7). This review deals w i t h t u m o r promoters isolated from marine organisms, such as lyngbyatoxin A , also named teleocidin A - l , aplysiatoxins, palytoxin, and okadaic acid (Figure 1). It is noteworthy that lyngbyatoxin A , debromoaplysiatoxin, aplysiatoxin, and okadaic acid have the same potent tumor p r o m o t i n g activities as T P A i n two-stage carcinogenesis experiments (8,9,10).

TPA-Type Tumor Promoters: Teleocidin Class Teleocidin isolated from Streptomyces mediocidicus is a mixture o f two isomers o f teleocidin A and four isomers o f teleocidin B (Figure 1 a n d Table I) (11,12). (-)Indolactam-V is a biosynthetic intermediate o f teleocidins A and B (13). D e s - O methylolivoretin C is a regioisomer o f teleocidin B - l (Table I) (14). Lyngbyatoxin A was isolated from a H a w a i i a n shallow-water variety o f Lyngbya majuscula, which grows at K a h a l a Beach o n the island o f O a h u (15). I n 1979, Cardellina et a l . determined the structure o f lyngbyatoxin A (Figure 1). Because lyngbyatoxin A was structurally similar to teleocidin B , and was a highly inflammatory a n d vesicatory substance like teleocidin B , we thought that lyngbyatoxin A might be as active as teleocidin B i n various biological and biochemical tests and i n a two-stage carcinogenesis experiment o n mouse skin. However, we found that lyngbyatoxin A is identical to o n e o f the two isomers o f teleocidin A , teleocidin A - l , w h i c h corresponds to (19R)-teleocidin A (16). Lyngbyatoxin A was biologically and biochemically active like a l l isomers o f teleocidins A a n d B . Table II shows that lyngbyatoxin A h a d approximately the same potency as T P A i n an irritant test o n mouse ear, i n inductions o f ornithine decarboxylase ( O D C ) i n mouse skin and adhesion o f h u m a n promyelocytic leukemia ( H L - 6 0 ) cells, i n i n h i b i t i o n o f the specific binding o f H - T P A to a mouse skin particulate fraction, a n d i n activation o f protein kinase C i n vitro. A n irritant test o n mouse ear shows the inflammatory effect. Induction o f O D C i n mouse skin reflects the induction o f polyamine biosynthesis associated with cell proliferation. Induction o f cell adhesion o f H L - 6 0 cells is a measure o f changes o f the cell surface induced by a t u m o r promoter. I n h i b i t i o n o f the specific binding o f H - T P A to a mouse skin particulate fraction measures the p h o r b o l ester receptor binding o f a c o m p o u n d . I n a two-stage carcinogenesis experiment, lyngbyatoxin A had the same potent t u m o r p r o m o t i n g activity as T P A , as shown i n Table II, as d i d teleocidin A - 2 and the four teleocidin B isomers (data n o t shown). T h e two-stage carcinogenesis experiment was carried o u t by a single application o f 100 pg D M B A , followed by repeated applications o f the test compounds i n the amounts shown i n Table II, twice a week, u n t i l week 30. T u m o r p r o m o t i n g activity was determined as the percentage o f tumor-bearing mice i n the group treated w i t h D M B A plus the test c o m p o u n d (Table II) (77). 3

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TPA-Type Tumor Promoters: Aplysiatoxin Class Aplysiatoxin and debromoaplysiatoxin were isolated from another variety o f bluegreen alga at K a i l u a Beach o n the windward side o f O a h u found to be a causative agent o f swimmer's itch (78). Aplysiatoxin and debromoaplysiatoxin were also isolated from blue-green alga i n O k i n a w a (79). I n addition to aplysiatoxin and debromoaplysiatoxin, bromoaplysiatoxin, oscillatoxin A and anhydrodebromoaplysiatoxin were also obtained from a mixture o f blue-green algae (20). Dibromoaplysiatoxin, w h i c h contains three bromine atoms, is a chemically brominated derivative o f

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Lyngbyatoxin A

(B-1 , B - 2 , B - 3 , B - 4 )

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Table I. New Tumor Promoters Classified According to Their Sources 3. From marine organisms 1. From Actinomycetes Teleocidin A - l , A - 2 Teleocidin B - 1 , B - 2 , B - 3 , B - 4 (-)-Indolactam-V Des-O-methylolivoretin C

2. From terrestrial plants Thapsigargin

Lyngbyatoxin A (Teleocidin A - l ) Debromoaplysiatoxin Aplysiatoxin Bromoaplysiatoxin Dibromoaplysiatoxin Oscillatoxin A Anhydrodebromoaplysiatoxin Palytoxin Okadaic acid

In Marine Toxins; Hall, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

In Marine Toxins; Hall, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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Tumor promoter

Table II. Effects of New Tumor Promoters Derived from Marine Organisms

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New Tumor Promoters from Marine Natural Products 237

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debromoaplysiatoxin (27). T h e effects o f these compounds o n the activities tested are summarized i n Table II. T h e results for O D C induction a n d t u m o r p r o m o t i n g activity were obtained with o p t i m a l concentrations o f the compounds. L i k e lyngbyatoxin A , the aplysiatoxin class tumor promoters b i n d to p h o r b o l ester receptors i n the cell membrane and activate protein kinase C i n vitro (Table II). Interestingly, a l l compounds o f the aplysiatoxin class were found to be t u m o r promoters w i t h varying potencies o f tumor p r o m o t i n g activity (Table II). However, it is important to describe the potency o f anhydrodebromoaplysiatoxin regarding several biological effects i n more detail. Anhydrodebromoaplysiatoxin was reported to be an inactive c o m p o u n d formed by a facile, acid-catalyzed dehydration o f debromoaplysiatoxin (22). Table II shows that 0.1 n m o l o f anhydrodebromoaplysiatoxin was negative i n irritant test o n mouse ear and o u r earlier paper reported that 3 n m o l o f anhydrodebromoaplysiatoxin d i d n o t induce any O D C activity (10). However, 90 n m o l o f the c o m p o u n d induced 2.02 n m o l C O ^ m g protein as shown i n Table II. A d d i t i o n a l results o f several experiments, such as induct i o n o f H L - 6 0 cell adhesion and activation o f protein kinase C , suggested the presence o f weak biological activity i n anhydrodebromoaplysiatoxin, which was also supported by the evidence o f i n h i b i t i o n o f metabolic cooperation i n the Chinese hamster V 7 9 cell system found by Trosko and his associates (23). T h e two-stage carcinogenesis experiments with D M B A plus anhydrodebromoaplysiatoxin using two different doses, 4 n m o l and 20 n m o l , revealed that the percentages o f tumor promoting activity were 0 % and 4 0 % i n week 30, respectively. It was therefore concluded that anhydrodebromoaplysiatoxin is a derivative associated w i t h a weak activity. Furthermore, experiments with H-TPA, H-lyngbyatoxin A, and H debromoaplysiatoxin indicated three classes o f tumor promoters that b i n d to the same p h o r b o l ester receptors i n cell membranes i n the same way (24). Since lyngbyatoxin A and the aplysiatoxin class exert tumor p r o m o t i n g activity through the same pathway as T P A , we called them T P A - t y p e tumor promoters (6). 3

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Non-TPA Type Tumor Promoters: Palytoxin and Okadaic Acid Class In contrast to the T P A - t y p e tumor promoters, palytoxin, thapsigargin, and okadaic acid are classified as n o n - T P A type tumor promoters, which do not b i n d to p h o r b o l ester receptors, o r activate protein kinase C i n vitro (Table II) (6,25-27). I n this chapter, thapsigargin is not discussed, because it is derived from terrestrial plants. Palytoxin was isolated from a marine coelenterate o f the genus Palythoa (Figure 1) (28,29). Okadaic acid was isolated from a black sponge, Halichondria okadai (Figure 1) (30). Okadaic acid is a polyether derivative o f a C fatty acid. A s Table II shows, palytoxin and okadaic acid both caused irritation o f mouse ear. Palytoxin d i d not induce O D C i n mouse skin o r H L - 6 0 cell adhesion, whereas okadaic acid induced O D C i n mouse skin, but not H L - 6 0 cell adhesion (Table II) (23,31). L i k e the T P A - t y p e tumor promoters, palytoxin and okadaic acid stimulated prostaglandin E production from H - a r a c h i d o n i c acid-prelabeled macrophages and arachidonic acid metabolism by rat liver cells i n culture (data not shown) (32,33). Palytoxin was shown to be the strongest prostaglandin inducer found to date. It is noteworthy that palytoxin and okadaic acid exert various effects and t u m o r promoting activities; however, they may not exert their effects by the same pathway. O k a daic acid acts o n cells i n a different way from T P A - t y p e t u m o r promoters, such as T P A , lyngbyatoxin A , and aplysiatoxin, but its tumor p r o m o t i n g activity is as strong as that o f T P A - t y p e tumor promoters (27). Therefore, the mechanism o f action o f okadaic acid is o f interest. 3

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W e synthesized H - o k a d a i c acid chemically and demonstrated its specific binding to the particulate and cytosolic fractions o f mouse skin. T h e specific binding o f H - o k a d a i c acid to the particulate fraction was not inhibited by T P A , lyngbyatoxin

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A , aplysiatoxin, o r palytoxin. Therefore, we proposed that okadaic acid binds to its o w n receptor and induces various biological effects, including t u m o r p r o m o t i n g activity, through this receptor (27). W e are n o w investigating the nature o f its receptor. In addition to okadaic acid, dinophysistoxin-1 (i.e., 35-methylokadaic acid), 7 - 0 palmitoyl-okadaic acid, and pectenotoxin 2 are reported to be diarrhetic toxins from shellfish (34). A p p l i c a t i o n o f 1 / i g o f dinophysistoxin-1 to mouse ear caused as strong irritation as the same dose o f okadaic acid. Interestingly, the potencies o f these compounds i n the irritant test o n mouse ear correlated well w i t h their potencies as diarrhetic shellfish poisons. Dinophysistoxin-1 induced O D C activity as strongly as okadaic acid. Recently, w e found that dinophysistoxin-1 is also a new n o n - T P A type tumor promoter w i t h as high activity as okadaic acid (35).

Common Effects of Tumor Promoters W e have shown that T P A - t y p e tumor promoters, such as lyngbyatoxin A and aplysiatoxins exert tumor p r o m o t i n g activities o n mouse skin through different mechanisms from those o f n o n - T P A type tumor promoters such as palytoxin, okadaic acid, and dinophysistoxin-1. Furthermore, we found that the two types o f tumor promoters induced c o m m o n biological effects, such as irritation o f mouse ear, and stimulation o f prostaglandin E production and o f arachidonic acid metabolism i n rat macrophages. These c o m m o n effects seem to be the most essential biological activities i n tumor p r o m o t i o n (6). This chapter reports the presence o f various kinds o f t u m o r promoters i n marine organisms. T h e problem o f the biological functions o f these tumor promoters remains to be investigated. S o l u t i o n o f this problem w i l l throw light o n the problems o f tumor p r o m o t i o n and tumor development. W e are also investigating inhibitors o f tumor p r o m o t i o n derived from marine organisms (36). This w o r k shows that marine natural products provide useful tools for understanding chemical carcinogenesis. 2

Acknowledgments This w o r k was supported i n part by G r a n t s - i n - A i d for Cancer Research from the M i n i s t r y o f E d u c a t i o n , Science and Culture, a grant for the Program for a Comprehensive 10-Year Strategy for Cancer C o n t r o l from the M i n i s t r y o f H e a l t h and Welfare o f Japan, grants from the F o u n d a t i o n for P r o m o t i o n o f Cancer Research, the Princess Takamatsu Cancer Research F o u n d a t i o n , and the S m o k i n g Research Foundation., and by G r a n t C A 12623 from the N a t i o n a l Institutes o f Health. Literature Cited 1. 2. 3.

4. 5. 6. 7.

Berenblum, I. Cancer Res. 1941, 1, 44. Balmain, A ; Ramsden, M.; Bowden, G.T.; Smith, J. Nature 1984, 307, 658. Boutwell, R.K. In Carcinogenesis: Mechanisms of Tumor Promotion and Cocarcinogenesis; Slaga, T.J., Sivak, A , Boutwell, R.K., Eds.; Raven Press: New York, 1978: Vol. 2, p 49. Hecker, E . Methods Cancer Res. 1971, 6, 439. Van Duuren, B.L. Prog. Exp. Tumor Res. 1969, 11, 31. Fujiki, H.; Sugimura, T. Adv. Cancer Res. 1987, 49, 223. Fujiki, H.; Suganuma, M.; Hirota, M.; Yoshizawa, S.; Suguri, H.; Suttajit, M.; Wongchai, V.; Sugimura, T. In Current Status of Cancer Research in Asia, The

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12. 13. 14.

15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

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Middle East and Other Countries; Wada, T., Aoki, K., Yachi, A., Eds.; The University of Nagoya Press: Nagoya, 1987; p 215. Fujiki, H.; Suganuma, M.; Hakii, H.; Bartolini, G.; Moore, R.E.; Takayama, S.; Sugimura, T. J. Cancer Res. Clin. Oncol. 1984, 108, 174. Moore, R.E. In Cellular Interactions by Environmental Tumor Promoters; Fujiki, H., Hecker, E., Moore, R.E., Sugimura, T., Weinstein, I.B., Eds; Jpn. Sci. Soc. Press, Tokyo/VNU Science Press: Utrecht, 1984: p 49. Suganuma, M.; Fujiki, H.; Tahira, T.; Cheuk, C.; Moore, R.E.; Sugimura, T. Carcinogenesis 1984, 5, 315. Fujiki, H.; Suganuma, M.; Tahira, T.; Yoshioka, A.; Nakayasu, M.; Endo, Y.; Shudo, K.; Takayama, S.; Moore, R.E.; Sugimura, T. In Cellular Interactions by Environmental Tumor Promoters; Fujiki, H., Hecker, E., Moore, R.E., Sugimura, T., Weinstein, I.B., Eds; Jps. Sci. Soc. Press, Tokyo/VNU Science Press: Utrecht, 1984: p 37. Fujiki, H.; Sugimura, T. Cancer Surveys 1983, 2, 539. Fujiki, H.; Suganuma, M.; Hakii, H.; Nakayasu, M.; Endo, Y.; Shudo, K.; Irie, K.; Koshimizu, K.; Sugimura, T. Proc. Jpn.Acad.1985, 61, 45. Ninomiya, M.; Fujiki, H.; Paik, N.S.; Hakii, H.; Suganuma, M.; Hitotsuyanagi, Y.; Aimi, N.; Sakai, S.; Endo, Y.; Shudo, K.; Sugimura, T. Jpn. J. Cancer Res. (Gann) 1986, 77, 222. Cardellina, J.H.; Marner, F.-J.II; Moore, R.E. Science 1979, 204, 193. Sakai, S.; Hitotsuyanagi, Y.; Aimi, N.; Fujiki, H.; Suganuma, M.; Sugimura, T.; Endo, Y.; Shudo, K. Tetrahedron Lett. 1986, 27, 5219. Fujiki, H.; Suganuma, M.; Matsukura, N.; Sugimura, T.; Takayama, S. Carcinogenesis 1982, 3, 895. Moore, R.E. Pure Appl. Chem. 1982, 54, 1919. Fujiki, H.; Ikegami, K.; Hakii, H.; Suganuma, M.; Yamaizumi, Z.; Yamazato, K.; Moore, R.E.; Sugimura, T. Jpn. J. Cancer Res. (Gann) 1985, 76, 257. Mynderse, J.S.; Moore, R.E. J. Org. Chem. 1978, 43, 2301. Moore, R.E.; Blackman, A.J.; Cheuk, C.E.; Mynderse, J.S.; Matsumoto, G.K.; Clardy, J.; Woodard, R.W.; Craig, J.C. J. Org. Chem. 1984, 49, 2484. Kato, Y.; Scheuer, P.J. Pure Appl. Chem. 1976, 48, 29. Jone, C.; Erickson, L.; Trosko, J.E.; Chang, C.C. Cell Biology and Toxicology 1987, 3, 1. Moore, R.E.; Patterson, G.M.; Entzeroth, M.; Morimoto, H.; Suganuma, M.; Hakii, H.; Fujiki, H.; Sugimura, T. Carcinogenesis 1986, 7, 641. Fujiki, H.; Suganuma, M.; Nakayasu, M.; Hakii, H.; Horiuchi, T.; Takayama, S.; Sugimura, T. Carcinogenesis 1986, 7, 707. Hakii, H.; Fujiki, H.; Suganuma, M.; Nakayasu, M.; Tahira, T.; Sugimura, T.; Scheuer, P.J.; Christensen, S.B. J. Cancer Res. Clin. Oncol. 1986, 111, 177. Suganuma, M.; Fujiki, H.; Suguri, H.; Yoshizawa, S.; Hirota, M.; Nakayasu, M.; Ojika, M.; Wakamatsu, K.; Yamada, K.; Sugimura, T. Proc. Natl. Acad. Sci. U.SA. 1988, 85, 1768. Moore, R.E.; Bartolini, G. J. Am. Chem. Soc. 1981, 103, 2491. Uemura, D.; Ueda, K.; Hirata, Y.; Naoki, H.; Iwashita, T. Tetrahedron Lett. 1981, 22, 2781. Tachibana, K.; Scheuer, P.J.; Tsukitani, Y.; Kikuchi, H.; Van Engen D.; Clardy, J.; Gopichand, Y.; Schmitz, F.J. J. Am. Chem. Soc. 1981, 103, 2469. Fujiki, H.; Suganuma, M.; Suguri, H.; Yoshizawa, S.; Ojika, M.; Wakamatsu, K.; Yamada, K.; Sugimura, T. Proc. Jpn.Acad.1987, 63, 51. Ohuchi, K.; Watanabe, M.; Yoshizawa, K.; Tsurufuji, S.; Fujiki, H.; Suganuma, M.; Sugimura, T.; Levine, L. Biochim. Biophys. Acta 1985, 834, 42. Levine, L.; Fujiki, H. Carcinogenesis 1985, 6, 1631.

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Murata, M.; Shimatani, M.; Sugitani, H.; Oshima, Y.; Yasumoto, T. Bull. Jpn. Soc. Fish 1982, 48, 549. 35. Fujiki, H.; Suganuma, M.; Suguri, M.; Yoshizawa, S.; Takagi, K.; Uda, N.; Wakamatsu, K.; Yamada, K.; Murata, M.; Yasumoto, T.; Sugimura, T. Jpn. J. Cancer Res. (Gann) 1988, 79, 1089. 36. Fujiki, H., Moore, R.E. Jpn. J. Cancer Res. (Gann) 1987, 78, 875.

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RECEIVED June 12, 1989

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