Membrane transport and antitumor activity of pirarubicin, and comparison with those of doxorubicin
Open accessAbstract
We have compared the membrane transport and antitumor activity of pirarubicin with those of doxorubicin in M5076 ovarian sarcoma, which exhibits low sensitivity to doxorubicin. Pirarubicin was rapidly taken up by M5076 cells and the intracellular concentration of pirarubicin reached more than 2.5‐fold that of doxorubicin. In terms of the 50% cell growth‐inhibitory concentration in vitro, pirarubicin was more effective than doxorubicin. Thus, the intracellular concentration influenced the cytotoxicity of these anthracycline agents. On comparison of the nuclear uptake of pirarubicin and doxorubicin, the nucleus/cell ratio of pirarubicin was found to be about 40%, whereas that of doxorubicin reached more than 80%. As the intranuclear concentration of pirarubicin is dependent on nuclear transport, the increases in not only cell membrane transport, but also nuclear membrane transport contributed to the enhancement of the efficacy of pirarubicin. In M5076 solid tumor‐bearing mice, pirarubicin reduced the tumor weight to 60% of the control level, although doxorubicin had no effect. These results were supported by the intracellular uptake of pirarubicin. Moreover, theanine, which inhibited the pirarubicin efflux from M5076 cells, increased by 1.3‐fold the pirarubicin concentration in the tumor and enhanced the therapeutic efficacy of pirarubicin 1.7‐fold. In conclusion, our results suggest that an increase in the concentration of an anthracycline derivative in tumor cells due to alteration of cell membrane transport results in enhancement of the antitumor activity.
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Theanine inhibits efflux of chemotherapeutic agents such as doxorubicin, idarubicin, cisplatin, and irinotecan, causing them to accumulate in tumor cells and protecting normal cells through antioxidant property and maintenance of cellular GSH.
“The efflux of chemotherapeutic agents (e.g.doxorubicin, idarubicin, cisplatin, irinotecan) are inhibited by theanine, which causes them to accumulate in tumor cells and to protect normal cells from damage by these drugs through its antioxidant property and maintaining cellular GSH level [22,[27][28][29] .”
From l -theanine: A potential multifaceted natural bioactive amide as health supplement (2017) · cites this paper as [28]
L-theanine competitively inhibits glutamate transport into infected tumor cells and can decrease intracellular glutathione levels.
“L-theanine, as chemotherapeutic agent, competitively inhibits glutamate transport into the infected tumor cells, can also decrease intracellular glutathione (GSH) levels.”
From l -theanine: A potential multifaceted natural bioactive amide as health supplement (2017) · cites this paper as [28]
Theanine inhibits biosynthesis of the glutamate transport protein and intracellular glutathione, resulting in less glutathione doxorubicin conjugate of the MRP5/GS-X pump and less intercellular transport of doxorubicin, which is beneficial for anti-tumor drugs.
“First, Theanine inhibits biosynthesis of the glutamate transport protein and intracellular glutathione, resulting in less glutathione doxorubicin conjugate (GS-DOX) of the multidrug resistance-associated protein-5/GS-X (MRP5/GS-X) pump, and less intercellular transport of doxorubicin (DOX), which is beneficial in effect of anti-tumor drugs [28,50] .”
From l -theanine: A potential multifaceted natural bioactive amide as health supplement (2017) · cites this paper as [28]
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Cites
Green tea composition, consumption, and polyphenol chemistry
Graham, H. N. (1992) · Preventive Medicine · doi:10.1016/0091-7435(92)90041-f · Cited by 1,889 · see citing works
Hamada, H., & TSURUO, T. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.20.7785 · Cited by 560 · see citing works
Cell biological mechanisms of multidrug resistance in tumors.
Simon, S. M., & Schindler, M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.9.3497 · Cited by 370 · see citing works
Pieters, R., Huismans, D. R., Loonen, A. H., Veerman, A. J. P., Hählen, K., den Berg, A. V. D. D.-V., & Wering, E. R. (1991) · The Lancet · doi:10.1016/0140-6736(91)91029-t · Cited by 216 · see citing works
Metastatic behavior of a murine reticulum cell sarcoma exhibiting organ-specific growth.
Hart, I. R., Talmadge, J. E., & Fidler, I. J. (1981) · PubMed · Cited by 154 · see citing works
4'-O-tetrahydropyranyladriamycin as a potential new antitumor agent.
Tsuruo, T., Iida, H., Tsukagoshi, S., & Sakurai, Y. (1982) · PubMed · Cited by 110 · see citing works
Rapid uptake by cultured tumor cells and intracellular behavior of 4'-O-tetrahydropyranyladriamycin.
Kunimoto, S., MIURA, K., Takahashi, Y., TAKEUCHI, T., & UMEZAWA, H. (1983) · The Journal of Antibiotics · doi:10.7164/antibiotics.36.312 · Cited by 86 · see citing works
Modulation of cancer chemotherapy by green tea.
Sadzuka, Y., Sugiyama, T., & Hirota, S. (1998) · PubMed · Cited by 80 · see citing works
Self-citationCharacterization of a murine ovarian reticulum cell sarcoma of histiocytic origin.
Talmadge, J. E., Key, M. E., & Hart, I. R. (1981) · PubMed · Cited by 78 · see citing works
The effects of theanine, as a novel biochemical modulator, on the antitumor activity of adriamycin
Sadzuka, Y., Sugiyama, T., Miyagishima, A., Nozawa, Y., & Hirota, S. (1996) · Cancer Letters · doi:10.1016/0304-3835(96)04282-6 · Cited by 68 · see citing works
Self-citationGoren, D., Gabizón, A., & Barenholz, Y. (1990) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(90)90165-k · Cited by 63 · see citing works
Sugiyama, T., & Sadzuka, Y. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00185-2 · Cited by 63 · see citing works
Self-citationSadzuka, Y., Nakai, S.-I., Miyagishima, A., Nozawa, Y., & Hirota, S. (1995) · Journal of drug targeting · doi:10.3109/10611869509015930 · Cited by 33 · see citing works
Self-citationNagasawa, K., Natazuka, T., Chihara, K., Kitazawa, F., Tsumura, A., Takara, K., Nomiyama, M., Ohnishi, N., & Yokoyama, T. (1996) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s002800050389 · Cited by 30 · see citing works
Self-citationNagasawa, K., Ohnishi, N., & Yokoyama, T. (1997) · Japanese Journal of Cancer Research · doi:10.1111/j.1349-7006.1997.tb00447.x · Cited by 17 · see citing works
Self-citationNagasawa, K., Ohnishi, N., & Yokoyama, T. (1998) · Japanese Journal of Cancer Research · doi:10.1111/j.1349-7006.1998.tb03270.x · Cited by 12 · see citing works
Self-citationTalmadge, J. E., & Hart, I. R. (1983) · Veterinary Pathology · doi:10.1177/030098588302000310 · Cited by 12 · see citing works
Nagasawa, K., Natazuka, T., Nomiyama, M., Ohnishi, N., & Yokoyama, T. (1996) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.19.100 · Cited by 10 · see citing works
Self-citationThe Study of Polyethyleneglycol-Coated Liposomes Containing CPT-11
Sadzuka, Y., Hirotsu, S., Miyagishima, A., Nozawa, Y., & Hirota, S. (1997) · Journal of Liposome Research · doi:10.3109/08982109709035500 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Chemosensitization and Radiosensitization of Tumors by Plant Polyphenols
Garg, A. K., Buchholz, T. A., & Aggarwal, B. B. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.1630 · Cited by 277 · see citing works
Itoh, M., Kitano, T., Watanabe, M., Kondo, T., Yabu, T., Taguchi, Y., Iwai, K., Tashima, M., Uchiyama, T., & Okazaki, T. (2003) · PubMed · Cited by 148 · see citing works
Potential Bioactive Components and Health Promotional Benefits of Tea ( Camellia sinensis )
Samanta, S. (2020) · Journal of the American Nutrition Association · doi:10.1080/07315724.2020.1827082 · Cited by 142 · see citing works
Liu, Q., Duan, H., Luan, J., Yagasaki, K., & Zhang, G. (2009) · Cytotechnology · doi:10.1007/s10616-009-9223-y · Cited by 83 · see citing works
Sugiyama, T., & Sadzuka, Y. (2003) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(03)00031-3 · Cited by 75 · see citing works
Self-citationl -theanine: A potential multifaceted natural bioactive amide as health supplement
Adhikary, R., & Mandal, V. (2017) · Asian Pacific Journal of Tropical Biomedicine · doi:10.1016/j.apjtb.2017.08.005 · Cited by 55 · see citing works
Desai, M. J., & Armstrong, D. W. (2004) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.1319 · Cited by 54 · see citing works
Daruwalla, J., Nikfarjam, M., Greish, K. F., Malcontenti‐Wilson, C., Muralidharan, V., Christophi, C., & Maeda, H. (2010) · Cancer Science · doi:10.1111/j.1349-7006.2010.01619.x · Cited by 53 · see citing works
Lehmann, M., Franco, A., Vilar, K. D. S. P., Reguly, M. L., & de Andrade, H. H. R. (2003) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/s1383-5718(03)00162-1 · Cited by 48 · see citing works
Zhang, G., Ye, X., Ji, D., Zhang, H., Sun, F., Shang, C., Zhang, Y., Wu, E., Wang, F., Wu, F., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2336 · Cited by 47 · see citing works
Trudel, D., Labbé, D. P., Bairati, I., Fradet, V., Bazinet, L., & Têtu, B. (2012) · Gynecologic Oncology · doi:10.1016/j.ygyno.2012.04.048 · Cited by 47 · see citing works
Nakamura, H., Randárová, E., Chytil, P., Tsukigawa, K., Fang, J. Q., Haratake, M., Ulbrich, K., Etrych, T., & Maeda, H. (2016) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b00697 · Cited by 46 · see citing works
L-theanine and immunity: a review
Chen, S., Kang, J., Zhu, H., Wang, K., Han, Z., Wang, L., Liu, J., Wu, Y., He, P., Tu, Y., et al. (2023) · Molecules · doi:10.3390/molecules28093846 · Cited by 44 · see citing works
Liu, J., Sun, Y., Zhang, H., Ji, D., Wu, F., Tian, H., Liu, K., Zhang, Y., Wu, B., & Zhang, G. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.09.007 · Cited by 38 · see citing works
Randárová, E., Janoušková, O., Cuchalová, L., Hvězdová, Z. (., Hraběta, J., Eckschlager, T., Sivák, L., Ulbrich, K., Etrych, T., & Šubr, V. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.05.036 · Cited by 34 · see citing works
Daruwalla, J., Greish, K. F., Nikfarjam, M., Millar, I., Malcontenti‐Wilson, C., Iyer, A. K., & Christophi, C. (2007) · Journal of drug targeting · doi:10.1080/10611860701499839 · Cited by 33 · see citing works
Chabchoubi, I. B., Lam, S. S., Pane, S. E., Ksibi, M., Guerriero, G., & Hentati, O. (2022) · Environmental Pollution · doi:10.1016/j.envpol.2022.120698 · Cited by 29 · see citing works
Preparation and pharmacokinetics of pirarubicin loaded dehydration–rehydration vesicles
Kawano, K. (2003) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(02)00628-2 · Cited by 28 · see citing works
Zhang, H., Yang, J.-J., Lu, J.-P., Lai, C., Sheng, J., Li, Y.-X., Hao, Q., Zhang, S.-M., & Gupta, S. K. (2009) · CardioVascular and Interventional Radiology · doi:10.1007/s00270-009-9546-2 · Cited by 26 · see citing works
Zhang, G., Miura, Y., & Yagasaki, K. (2001) · Cytotechnology · doi:10.1023/a:1014005423181 · Cited by 23 · see citing works
Preparative Isolation and Purification of <scp>L</scp>‐Theanine by HPLC
Zhang, Y., Chen, B., Huang, Z., & Shi, Z. (2004) · Journal of Liquid Chromatography & Related Technologies · doi:10.1081/jlc-120029704 · Cited by 20 · see citing works
El‐Kawy, O. A., & Abdelaziz, G. (2021) · Applied Radiation and Isotopes · doi:10.1016/j.apradiso.2021.110007 · Cited by 18 · see citing works
Song, H. J., Kim, Y. D., Jeong, M. J., Ahn, M. S., Kim, S. W., Liu, J. R., & Choi, M. S. (2015) · Plant Biotechnology Reports · doi:10.1007/s11816-015-0344-9 · Cited by 18 · see citing works
Yoo, S. H., Jeong, C. W., Kwak, C. H., Kim, H. H., Choo, M. S., & Ku, J. H. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8071059 · Cited by 17 · see citing works
Nagai, K., Nagasawa, K., Sadzuka, Y., Tsujimoto, M., Takara, K., Ohnishi, N., Yokoyama, T., & Fujimoto, S. (2002) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-001-0404-4 · Cited by 14 · see citing works
Self-citationZhang, G., Li, Z., Wan, X., Zhang, Y., Zhu, R., Liu, Z., Ji, D., Zhang, H., Wu, F., Tian, H., et al. (2016) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.6b02509 · Cited by 14 · see citing works
Green Tea Catechins and L-Theanine in Integrative Cancer Care: A Review of the Research
Huber, L. G. (2003) · Alternative and Complementary Therapies · doi:10.1089/107628003322658557 · Cited by 13 · see citing works
Hall, W. C., Elder, B., Walker, C. L., Cai, S.-L., Peters, D. G., Goodman, D. G., Ulland, B. M., & Borzelleca, J. F. (2007) · Toxicologic Pathology · doi:10.1080/01926230601156252 · Cited by 12 · see citing works
Chemistry and Biological Properties of Theanine
Zhang, Z., Wan, X., & Li, D. (2008) · Nutraceutical science and technology · doi:10.1201/9781420008036.ch16 · Cited by 12 · see citing works
Makimoto, A., Fang, J. Q., & Maeda, H. (2021) · Cancers · doi:10.3390/cancers13153698 · Cited by 11 · see citing works
Structure-to-Efficacy Relationship of HPMA-Based Nanomedicines: The Tumor Spheroid Penetration Study
Kudláčová, J., Kotrchová, L., Kostka, L., Randárová, E., Filipová, M., Janoušková, O., Fang, J. Q., & Etrych, T. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12121242 · Cited by 9 · see citing works
Ji, D., Wang, Y., Zhang, H., Chen, L., Liu, X., Sun, F., Liu, K., Yao, J., & Zhang, G. (2013) · Cytotechnology · doi:10.1007/s10616-013-9641-8 · Cited by 9 · see citing works
Horvath, L. E., Konstantinov, S., Ilarionova, M., & Todorov, D. K. (2004) · Fitoterapia · doi:10.1016/j.fitote.2004.09.007 · Cited by 6 · see citing works
Daruwalla, J., Greish, K. F., Malcontenti‐Wilson, C., Muralidharan, V., Maeda, H., & Christophi, C. (2015) · Surgery · doi:10.1016/j.surg.2015.03.019 · Cited by 3 · see citing works
Deep learning-based prediction of chemical accumulation in a pathogenic mycobacteriumPreprint
Sullivan, M. R., & Rubin, E. J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.15.628588 · Cited by 3 · see citing works
Hasegawa, T., Tsukigawa, K., Commey, K. L., Sakuragi, M., Imoto, S., Taguchi, K., Nishi, K., Otagiri, M., & Yamasaki, K. (2023) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.c23-00701 · Cited by 2 · see citing works
Yamada, Y., Iwai, S., TSUBOI, A., Kurahashi, C., Ota, M., Matsuoka, T., Sanbe, T., & Oguchi, K. (2009) · The Showa University Journal of Medical Sciences · doi:10.15369/sujms.21.117 · Cited by 2 · see citing works
Lehmann, M. (2003) · Americanae (AECID Library)
Nasiroleslami, M., & Mohitmafi, S. (2015) · Archives of Advances in Biosciences · doi:10.22037/jps.v6i1.8187
Li, Y., Fan, M., Zhang, S., Meng, X., Zhou, H., & Dou, Q. (2022) · Research Square · doi:10.21203/rs.3.rs-1955988/v1
- Authors
- Sugiyama, T., Sadzuka, Y., Nagasawa, K., Ohnishi, N., Yokoyama, T., & Sonobe, T.
- Affiliations
- Shizuoka University (JP)
- Kyoto Pharmaceutical University (JP)
- Corresponding author
- Sadzuka, Yasuyuki
- ORCID
- Nagasawa, Kazuki
- Venue
- Japanese Journal of Cancer Research
- Publisher
- Wiley
- Published
- 1999-07
- Volume
- 90
- Issue
- 7
- Pages
- 775-780
- ISSN
- 0910-5050 (ISSN-L)
- PMC
- PMC5926135
- OpenAlex
- W1966061343
- Cited by
- 40
- References
- 19
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 0.28
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Japanese Journal of Cancer Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- pirarubicin, doxorubicin, anthracyclines, membrane transport, nuclear transport, intracellular drug accumulation, anticancer activity, drug efflux inhibition, theanine, tumor-bearing mice, drug resistance
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Antineoplastic Combined Chemotherapy Protocols, Biological Transport, Cell Division, Cell Membrane, Cell Nucleus, Doxorubicin, Drug Interactions, Female, Glutamates, Male, Neoplasm Transplantation, Ovarian Neoplasms, Sarcoma, Experimental, Tea, Tumor Cells, Cultured, Mice
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