The Journal of Physiological Sciences

, Volume 62, Issue 3, pp 251–257 | Cite as

Effect of ascorbic acid on reactive oxygen species production in chemotherapy and hyperthermia in prostate cancer cells

  • Hidenobu Fukumura
  • Motohiko Sato
  • Kyouhei Kezuka
  • Itaru Sato
  • Xianfeng Feng
  • Satoshi Okumura
  • Takayuki Fujita
  • Utako Yokoyama
  • Haruki Eguchi
  • Yoshihiro IshikawaEmail author
  • Tomoyuki Saito
Original Paper


Cellular reactive oxygen species (ROS) production is increased by both temperature and anticancer drugs. Antioxidants are known to suppress ROS production while cancer patients may take them as dietary supplement during chemotherapy and hyperthermic therapy. We examined changes in ROS production in prostate cancer cells in the presence of various anticancer drugs and antioxidants at different temperatures. ROS production was increased with temperature in cancer cells, but not in normal cells; this increase was potently inhibited by ascorbic acid. ROS production was also increased in the presence of some anticancer drugs, such as vinblastine, but not by others. Dietary antioxidant supplements, such as β-carotene, showed variable effects. Ascorbic acid potently inhibited ROS production, even in the presence of anticancer drugs, while β-carotene showed no inhibition. Accordingly, our results suggest that cancer patients should carefully choose antioxidants during their cancer chemotherapy and/or hyperthermic therapy.


Reactive oxygen species Prostate cancer cells Hyperthermia Ascorbic acid Anti-oxidants Anti-cancer drugs 


  1. 1.
    Johnson KA, Brown PH (2010) Drug development for cancer chemoprevention: focus on molecular targets. Semin Oncol 37(4):345–358PubMedCrossRefGoogle Scholar
  2. 2.
    Zhang H, Wang G, Yang H (2011) Drug delivery systems for differential release in combination therapy. Expert Opin Drug Deliv 8:171–190PubMedCrossRefGoogle Scholar
  3. 3.
    Suit HD, Shwayder M (1974) Hyperthermia: potential as an anti-tumor agent. Cancer 34:122–129PubMedCrossRefGoogle Scholar
  4. 4.
    Li LF, Wang HQ, Liu XM, Zhang HL, Qiu LH, Qian ZZ, Li W (2011) Nimotuzumab in combination with chemotherapy in patients with advanced non-small cell lung cancer. Zhonghua Zhong Liu Za Zhi 33:626–628PubMedGoogle Scholar
  5. 5.
    Rodriguez-Luccioni HL, Latorre-Esteves M, Mendez-Vega J, Soto O, Rodriguez AR, Rinaldi C, Torres-Lugo M (2011) Enhanced reduction in cell viability by hyperthermia induced by magnetic nanoparticles. Int J Nanomed 6:373–380Google Scholar
  6. 6.
    Chen F, Wang CC, Kim E, Harrison LE (2008) Hyperthermia in combination with oxidative stress induces autophagic cell death in HT-29 colon cancer cells. Cell Biol Int 32:715–723PubMedCrossRefGoogle Scholar
  7. 7.
    Hurwitz MD, Hansen JL, Prokopios-Davos S, Manola J, Wang Q, Bornstein BA, Hynynen K, Kaplan ID (2011) Hyperthermia combined with radiation for the treatment of locally advanced prostate cancer: long-term results from Dana–Farber Cancer Institute study 94–153. Cancer 117:510–516PubMedCrossRefGoogle Scholar
  8. 8.
    Arai Y, Kondo T, Tanabe K, Zhao QL, Li FJ, Ogawa R, Li M, Kasuya M (2002) Enhancement of hyperthermia-induced apoptosis by local anesthetics on human histiocytic lymphoma U937 cells. J Biol Chem 277:18986–18993PubMedCrossRefGoogle Scholar
  9. 9.
    Chan SW, Nguyen PN, Ayele D, Chevalier S, Aprikian A, Chen JZ (2011) Mitochondrial DNA damage is sensitive to exogenous H(2)O(2) but independent of cellular ROS production in prostate cancer cells. Mutat Res 716:40–50PubMedCrossRefGoogle Scholar
  10. 10.
    Kurbacher CM, Wagner U, Kolster B, Andreotti PE, Krebs D, Bruckner HW (1996) Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro. Cancer Lett 103:183–189PubMedCrossRefGoogle Scholar
  11. 11.
    Kim IS, Jin JY, Lee IH, Park SJ (2004) Auranofin induces apoptosis and when combined with retinoic acid enhances differentiation of acute promyelocytic leukaemia cells in vitro. Br J Pharmacol 142:749–755PubMedCrossRefGoogle Scholar
  12. 12.
    Yeh SL, Wang WY, Huang CS, Hu ML (2006) Flavonoids suppresses the enhancing effect of beta-carotene on DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A549 cells. Chem Biol Interact 160:175–182PubMedCrossRefGoogle Scholar
  13. 13.
    Heaney ML, Gardner JR, Karasavvas N, Golde DW, Scheinberg DA, Smith EA, O’Connor OA (2008) Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 68:8031–8038PubMedCrossRefGoogle Scholar
  14. 14.
    Maluta S, Dall’oglio S, Nadalini L (2010) Treatment for intermediate and high-risk prostate cancer: controversial issues and the role of hyperthermia. Int J Hyperthermia 26:765–774PubMedCrossRefGoogle Scholar
  15. 15.
    Venkataraman S, Wagner BA, Jiang X, Wang HP, Schafer FQ, Ritchie JM, Patrick BC, Oberley LW, Buettner GR (2004) Overexpression of manganese superoxide dismutase promotes the survival of prostate cancer cells exposed to hyperthermia. Free Radic Res 38:1119–1132PubMedCrossRefGoogle Scholar
  16. 16.
    Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA (2005) Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase. Proc Natl Acad Sci USA 102:437–442PubMedCrossRefGoogle Scholar
  17. 17.
    Kuznetsov AV, Kehrer I, Kozlov AV, Haller M, Redl H, Hermann M, Grimm M, Troppmair J (2011) Mitochondrial ROS production under cellular stress: comparison of different detection methods. Anal Bioanal Chem 400:2383–2390PubMedCrossRefGoogle Scholar
  18. 18.
    Supabphol A, Muangman V, Chavasiri W, Supabphol R, Gritsanapan W (2009) N-acetylcysteine inhibits proliferation, adhesion, migration and invasion of human bladder cancer cells. J Med Assoc Thai 92:1171–1177PubMedGoogle Scholar
  19. 19.
    Jimenez-Aliaga K, Bermejo-Bescos P, Benedi J, Martin-Aragon S (2011) Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci 89:939–945PubMedCrossRefGoogle Scholar
  20. 20.
    Sinha BK, Mimnaugh EG (1990) Free radicals and anticancer drug resistance: oxygen free radicals in the mechanisms of drug cytotoxicity and resistance by certain tumors. Free Radic Biol Med 8:567–581PubMedCrossRefGoogle Scholar
  21. 21.
    Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418PubMedCrossRefGoogle Scholar
  22. 22.
    Alexandre J, Hu Y, Lu W, Pelicano H, Huang P (2007) Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res 67:3512–3517PubMedCrossRefGoogle Scholar
  23. 23.
    Fukui M, Yamabe N, Zhu BT (2010) Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells in vitro and in vivo. Eur J Cancer 46:1882–1891PubMedCrossRefGoogle Scholar
  24. 24.
    Narayana K (2010) Cisplatin induces duplex 3′ overhangs and 5′ blunt ends in epididymal epithelium in a Bax-dependent manner without any protection from l-ascorbic acid. Eur J Pharmacol 641:238–245PubMedCrossRefGoogle Scholar
  25. 25.
    Kim HJ, Lee JH, Kim SJ, Oh GS, Moon HD, Kwon KB, Park C, Park BH, Lee HK, Chung SY et al (2010) Roles of NADPH oxidases in cisplatin-induced reactive oxygen species generation and ototoxicity. J Neurosci 30:3933–3946PubMedCrossRefGoogle Scholar
  26. 26.
    Verrax J, Calderon PB (2008) The controversial place of vitamin C in cancer treatment. Biochem Pharmacol 76:1644–1652PubMedCrossRefGoogle Scholar
  27. 27.
    Jackson IL, Batinic-Haberle I, Sonveaux P, Dewhirst MW, Vujaskovic Z (2006) ROS production and angiogenic regulation by macrophages in response to heat therapy. Int J Hyperthermia 22:263–273PubMedCrossRefGoogle Scholar
  28. 28.
    Manda G, Nechifor MT, Neagu TM (2009) Reactive oxygen species, cancer and anti-cancer therapies. Curr Chem Biol 3:342–366CrossRefGoogle Scholar
  29. 29.
    Labriola D, Livingston R (1999) Possible interactions between dietary antioxidants and chemotherapy. Oncology (Williston Park) 13:1003–1008 (discussion 1008, 1011-1002)Google Scholar
  30. 30.
    Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C (2007) Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials. Cancer Treat Rev 33:407–418PubMedCrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer 2012

Authors and Affiliations

  • Hidenobu Fukumura
    • 1
  • Motohiko Sato
    • 2
  • Kyouhei Kezuka
    • 2
  • Itaru Sato
    • 2
  • Xianfeng Feng
    • 2
  • Satoshi Okumura
    • 2
  • Takayuki Fujita
    • 2
  • Utako Yokoyama
    • 2
  • Haruki Eguchi
    • 3
  • Yoshihiro Ishikawa
    • 2
    Email author
  • Tomoyuki Saito
    • 1
  1. 1.Department of Orthopaedic SurgeryYokohama City University School of MedicineYokohamaJapan
  2. 2.Cardiovascular Research InstituteYokohama City University School of MedicineYokohamaJapan
  3. 3.IHI CorporationYokohamaJapan

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