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Cancer Biomarkers for Integrative Oncology

  • Aniruddha GangulyEmail author
  • David Frank
  • Nagi Kumar
  • Yung-Chi Cheng
  • Edward Chu
Integrative Care (C Lammersfeld, Section Editor)
  • 122 Downloads
Part of the following topical collections:
  1. Topical Collection on Integrative Care

Abstract

Purpose of Review

There has been an increasing interest in using complementary and alternative medicine (CAM) approaches to treat cancer. It is therefore relevant and timely to determine if CAM biomarkers can be identified and developed to guide cancer diagnosis and treatment. Herein, we review the status of cancer biomarkers in CAM research and treatment to stimulate further research in this area.

Recent Findings

Studies on promising anti-cancer natural products, such as PHY906, honokiol, bryostatin-1, and sulforaphane have demonstrated the existence of potential cancer biomarker(s). Additional studies are required to further develop and ultimately validate these biomarkers that can predict clinical activity of the anti-cancer natural products used alone or in combination with chemotherapeutic agents.

Summary

A systematic approach is needed to identify and develop CAM treatment associated biomarkers and to define their role in facilitating clinical decision-making. The expectation is to use these biomarkers in determining potential options for CAM treatment, examining treatment effects and toxicity and/or clinical efficacy in patients with cancer.

Keywords

Biomarker Cancer complementary and alternative medicine (CAM) Integrative oncology Cancer diagnostics Anti-cancer natural product Anti-cancer herbal medicine 

Notes

Acknowledgements

The authors thank the past and present members of Dr. Y-C. Cheng’s laboratory group who were involved in the pre-clinical and translational studies on PHY906 and to all the clinical investigators, patients, and their families involved in the PHY906 clinical trials. The authors also thank Dr. Lyndsay Harris for the support and valuable comments, and to Dr. Laura K. Fogli for formatting this manuscript.

Funding Information

This research on PHY906 was supported in part by grants from the National Cancer Institute (grant nos. P01CA154295-01 and P30CA147904), the National Center for Complementary and Alternative Medicine, and a grant from the National Foundation for Cancer. Dr. David Frank was supported by NIH grant R01-CA160979.

Compliance with Ethical Standards

Conflict of Interest

Aniruddha Ganguly declares that he has no conflict of interest.

David Frank has received research funding from Gilead and Cstem; has received compensation from Kymera for service as a consultant; has a patent issued, licensed, and receives royalties for STAT Modulators; and has a patent pending for targeting the transcription factor NF-kB with harmine.

Nagi Kumar declares that she has no conflict of interest.

Yung-Chi Cheng is a fellow of the National Foundation for Cancer that partially supported PHY906 studies. He is a co-founder of Yiviva with the Yale University to further develop PHY906 (now known as Yiviva 906) for the treatment of various human cancers and other GI disorders.

Edward Chu is a member of the scientific advisory board of Yiviva.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, et al. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med. 2010;2(45):45ra59.PubMedCrossRefGoogle Scholar
  2. 2.
    Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269(2):199–225.PubMedCrossRefGoogle Scholar
  3. 3.
    Kunnumakkara AB, Bordoloi D, Harsha C, Banik K, Gupta SC, Aggarwal BB. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways. Clin Sci (Lond). 2017;131(15):1781–99.CrossRefGoogle Scholar
  4. 4.
    Samanta SK, Sehrawat A, Kim SH, Hahm ER, Shuai Y, Roy R, et al. Disease subtype-independent biomarkers of breast cancer chemoprevention by the ayurvedic medicine phytochemical withaferin A. J Natl Cancer Inst. 2017;109(6).Google Scholar
  5. 5.
    • Battle TE, Arbiser J, Frank DA. The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Blood. 2005;106(2):690–7 This study defined the molecular mechanism by which a natural product displays a therapeutic index in killing malignant B lymphocytes versus normal lymphocytes. It also showed how honokiol can overcome biologically important resistance mechanisms and synergize with conventional anti-cancer agents, all critical aspects for a novel therapeutic. PubMedCrossRefGoogle Scholar
  6. 6.
    Hsu HYH, C.S. Commonly used Chinese herb formulas with illustrations. Oriental Healing Art Institute: Long Beach; 1980.Google Scholar
  7. 7.
    Li S. The Ben Cao Gang Mu: Chinese dition Univ. California Press; 2016.Google Scholar
  8. 8.
    Tilton R, Paiva AA, Guan JQ, Marathe R, Jiang Z, van Eyndhoven W, et al. A comprehensive platform for quality control of botanical drugs (PhytomicsQC): a case study of Huangqin Tang (HQT) and PHY906. Chin Med. 2010;5:30.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ye M, Liu SH, Jiang Z, Lee Y, Tilton R, Cheng YC. Liquid chromatography/mass spectrometry analysis of PHY906, a Chinese medicine formulation for cancer therapy. Rapid Commun Mass Spectrom. 2007;21(22):3593–607.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang W, Saif MW, Dutschman GE, Li X, Lam W, Bussom S, et al. Identification of chemicals and their metabolites from PHY906, a Chinese medicine formulation, in the plasma of a patient treated with irinotecan and PHY906 using liquid chromatography/tandem mass spectrometry (LC/MS/MS). J Chromatogr A. 2010;1217(37):5785–93.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Lam W, Jiang Z, Guan F, Hu R, Liu SH, Chu E, et al. The number of intestinal bacteria is not critical for the enhancement of antitumor activity and reduction of intestinal toxicity of irinotecan by the Chinese herbal medicine PHY906 (KD018). BMC Complement Altern Med. 2014;14:490.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Liu SH, Cheng YC. Old formula, new Rx: the journey of PHY906 as cancer adjuvant therapy. J Ethnopharmacol. 2012;140(3):614–23.PubMedCrossRefGoogle Scholar
  13. 13.
    Lam W, Jiang Z, Guan F, Huang X, Hu R, Wang J, et al. PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment. Sci Rep. 2015;5:9384.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Farrell MP, Kummar S. Phase I/IIA randomized study of PHY906, a novel herbal agent, as a modulator of chemotherapy in patients with advanced colorectal cancer. Clin Colorectal Cancer. 2003;2(4):253–6.PubMedCrossRefGoogle Scholar
  15. 15.
    • Kummar S, Copur MS, Rose M, Wadler S, Stephenson J, O’Rourke M, et al. A phase I study of the chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer. Clin Colorectal Cancer. 2011;10(2):85–96 This was the first randomized, placebo-controlled clinical study to show that the Chinese herbal medicine PHY906 was able to significantly reduce the diarrhea, nausea/vomiting, and fatigue of irinotecan-based chemotherapy in patients with metastatic colorectal cancer. This study also showed that PHY906 did not alter the pharmacokinetic profile of the chemotherapy agents 5-fluorouracil and irinotecan. PubMedCrossRefGoogle Scholar
  16. 16.
    Saif MW, Lansigan F, Ruta S, Lamb L, Mezes M, Elligers K, et al. Phase I study of the botanical formulation PHY906 with capecitabine in advanced pancreatic and other gastrointestinal malignancies. Phytomedicine. 2010;17(3–4):161–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Yen Y, So S, Rose M, Saif MW, Chu E, Liu SH, et al. Phase I/II study of PHY906/capecitabine in advanced hepatocellular carcinoma. Anticancer Res. 2009;29(10):4083–92.PubMedGoogle Scholar
  18. 18.
    Saif M, Li J, Lamb L, Kaley K, Bussom S, Carbone R, et al. Phase II study of PHY906 plus capecitabine (CAP) in pts with gemcitabine-refractory pancreatic cancer (PC) and measurement of cytokines. J Clin Oncol. 2010;28(15_suppl):e14540-e.CrossRefGoogle Scholar
  19. 19.
    Alsamarai S, Ravage-Mass L, Kaley K, Dutschman G, Zhang W, Jiang Z, et al. A phase I study of PHY906 as a modulator of irinotecan (CPT-11) in patients with advanced solid tumors. J Clin Oncol. 2010;28(15_suppl):e13571-e.CrossRefGoogle Scholar
  20. 20.
    Bai X, Cerimele F, Ushio-Fukai M, Waqas M, Campbell PM, Govindarajan B, et al. Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J Biol Chem. 2003;278(37):35501–7.PubMedCrossRefGoogle Scholar
  21. 21.
    • Wang X, Beitler JJ, Huang W, Chen G, Qian G, Magliocca KR, et al. Honokiol radiosensitizes squamous cell carcinoma of the head and neck by downregulation of survivin. Clin Cancer Res. 2017; This study demonstrated that increased expression of the pro-survival protein survivin is a negative prognostic indicator in squamous cell carcinoma of the head and neck, and may mediate resistance to radiation therapy. Downregulation of survivin in response to the natural product honokiol sensitizes these cells to radiation, suggesting an innovative, rational way to therapeutically exploit the activity of this drug. Google Scholar
  22. 22.
    Avtanski BD, Arumugam N, Bonner MY, Arbiser JL, Saxena NK, Dipali S. Honokiol inhibits epithelial—mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis. Mol Oncol. 2014;8(3):565–80.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Pearson HE, Iida M, Orbuch RA, McDaniel NK, Nickel KP, Kimple RJ, et al. Overcoming resistance to cetuximab with honokiol, a small-molecule polyphenol. Mol Cancer Ther. 2017.Google Scholar
  24. 24.
    Jing P, Yongik L, Yian W, Ming Y. Honokiol targets mitochondria to halt cancer progression and metastasis. Mol Nutr Food Res. 2016;60(6):1383–95.CrossRefGoogle Scholar
  25. 25.
    Pan J, Lee Y, Zhang Q, Xiong D, Wan TC, Wang Y, et al. Honokiol decreases lung cancer metastasis through inhibition of the STAT3 signaling pathway. Cancer Prev Res. 2016.Google Scholar
  26. 26.
    Krige D. Traditional medicine and healers in South Africa. J Eur Med Writers Assoc. 2009.Google Scholar
  27. 27.
    Keck GE, Poudel YB, Cummins TJ, Rudra A, Covel JA. Total synthesis of bryostatin 1. J Am Chem Soc. 2011;133(4):744–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Matias D, Bessa C, Fátima Simões M, Reis CP, Saraiva L, Rijo P. Chapter 2 - Natural products as lead protein kinase c modulators for cancer therapy. In: Atta ur R, editor. Studies in natural products chemistry. 50: Elsevier; 2016. p. 45–79.Google Scholar
  29. 29.
    Kennedy MJ, Prestigiacomo LJ, Tyler G, May WS, Davidson NE. Differential effects of bryostatin 1 and phorbol ester on human breast cancer cell lines. Cancer Res. 1992;52(5):1278–83.PubMedGoogle Scholar
  30. 30.
    Khan TK, Nelson TJ. Protein kinase C activator bryostatin-1 modulates proteasome function. J Cell Biochem. 2018;119:6894–904.PubMedCrossRefGoogle Scholar
  31. 31.
    Jiang G, Dandekar S. Targeting NF-κB signaling with protein kinase C agonists as an emerging strategy for combating HIV latency. AIDS Res Hum Retrovir. 2015;31(1):4–12.PubMedCrossRefGoogle Scholar
  32. 32.
    • Battle TE, Frank DA. STAT1 mediates differentiation of chronic lymphocytic leukemia cells in response to bryostatin 1. Blood. 2003;102:3016–24 This study demonstrated that a natural product from a marine organism can have a unique mechanism as an anti-cancer therapeutic, by inducing the terminal differentiation of malignant cells. This approach holds the potential to be more effective and less toxic than standard cytotoxic therapies. This study also delineated the novel molecular pathway by which bryostatin 1 mediates this biological effect. PubMedCrossRefGoogle Scholar
  33. 33.
    Prendiville J, Crowther D, Thatcher N, Woll PJ, Fox BW, McGown A, et al. A phase I study of intravenous bryostatin 1 in patients with advanced cancer. Br J Cancer. 1993;68:418–24.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Jayson GC, Crowther D, Prendiville J, McGown AT, Scheid C, Stern P, et al. A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion. Br J Cancer. 1995;72:461–8.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci U S A. 1992;89(6):2399–403.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomark Prev. 1998;7(12):1091–100.Google Scholar
  37. 37.
    Fimognari C, Hrelia P. Sulforaphane as a promising molecule for fighting cancer. Mutat Res. 2007;635(2–3):90–104.PubMedCrossRefGoogle Scholar
  38. 38.
    Tang L, Zirpoli GR, Guru K, Moysich KB, Zhang Y, Ambrosone CB, et al. Consumption of raw cruciferous vegetables is inversely associated with bladder cancer risk. Cancer Epidemiol Biomark Prev. 2008;17(4):938–44.CrossRefGoogle Scholar
  39. 39.
    Tang L, Zirpoli GR, Guru K, Moysich KB, Zhang Y, Ambrosone CB, et al. Intake of cruciferous vegetables modifies bladder cancer survival. Cancer Epidemiol Biomark Prev. 2010;19(7):1806–11.CrossRefGoogle Scholar
  40. 40.
    Michaud DS, Clinton SK, Rimm EB, Willett WC, Giovannucci E. Risk of bladder cancer by geographic region in a U.S. cohort of male health professionals. Epidemiology. 2001;12(6):719–26.PubMedCrossRefGoogle Scholar
  41. 41.
    Michaud DS, Spiegelman D, Clinton SK, Rimm EB, Willett WC, Giovannucci E. Prospective study of dietary supplements, macronutrients, micronutrients, and risk of bladder cancer in US men. Am J Epidemiol. 2000;152(12):1145–53.PubMedCrossRefGoogle Scholar
  42. 42.
    Michaud DS, Spiegelman D, Clinton SK, Rimm EB, Willett WC, Giovannucci EL. Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J Natl Cancer Inst. 1999;91(7):605–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Veeranki OL, Bhattacharya A, Tang L, Marshall JR, Zhang Y. Cruciferous vegetables, isothiocyanates, and prevention of bladder cancer. Curr Pharmacol Rep. 2015;1(4):272–82.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Atwell LL, Zhang Z, Mori M, Farris P, Vetto JT, Naik AM, et al. Sulforaphane bioavailability and chemopreventive activity in women scheduled for breast biopsy. Cancer Prev Res (Phila). 2015;8(12):1184–91.CrossRefGoogle Scholar
  45. 45.
    Singh SV, Singh K. Cancer chemoprevention with dietary isothiocyanates mature for clinical translational research. Carcinogenesis. 2012;33(10):1833–42.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Tang L, Li G, Song L, Zhang Y. The principal urinary metabolites of dietary isothiocyanates, N-acetylcysteine conjugates, elicit the same anti-proliferative response as their parent compounds in human bladder cancer cells. Anti-Cancer Drugs. 2006;17(3):297–305.PubMedCrossRefGoogle Scholar
  47. 47.
    Zhang Y. Allyl isothiocyanate as a cancer chemopreventive phytochemical. Mol Nutr Food Res. 2010;54(1):127–35.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Houghton CA, Fassett RG, Coombes JS. Sulforaphane: translational research from laboratory bench to clinic. Nutr Rev. 2013;71(11):709–26.PubMedCrossRefGoogle Scholar
  49. 49.
    Choi S, Lew KL, Xiao H, Herman-Antosiewicz A, Xiao D, Brown CK, et al. D,L-Sulforaphane-induced cell death in human prostate cancer cells is regulated by inhibitor of apoptosis family proteins and Apaf-1. Carcinogenesis. 2007;28(1):151–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Gibbs A, Schwartzman J, Deng V, Alumkal J. Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 6. Proc Natl Acad Sci U S A. 2009;106(39):16663–8.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Gamet-Payrastre L, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, et al. Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells. Cancer Res. 2000;60(5):1426–33.PubMedGoogle Scholar
  52. 52.
    Suppipat K, Park CS, Shen Y, Zhu X, Lacorazza HD. Sulforaphane induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells. PLoS One. 2012;7(12):e51251.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jo GH, Kim GY, Kim WJ, Park KY, Choi YH. Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway. Int J Oncol. 2014;45(4):1497–506.PubMedCrossRefGoogle Scholar
  54. 54.
    Kensler TW, Egner PA, Agyeman AS, Visvanathan K, Groopman JD, Chen JG, et al. Keap1-nrf2 signaling: a target for cancer prevention by sulforaphane. Top Curr Chem. 2013;329:163–77.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Talalay P, Fahey JW. Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J Nutr. 2001;131(11 Suppl):3027S–33S.PubMedCrossRefGoogle Scholar
  56. 56.
    Dang YM, Huang G, Chen YR, Dang ZF, Chen C, Liu FL, et al. Sulforaphane inhibits the proliferation of the BIU87 bladder cancer cell line via IGFBP-3 elevation. Asian Pac J Cancer Prev. 2014;15(4):1517–20.PubMedCrossRefGoogle Scholar
  57. 57.
    Abbaoui B, Riedl KM, Ralston RA, Thomas-Ahner JM, Schwartz SJ, Clinton SK, et al. Inhibition of bladder cancer by broccoli isothiocyanates sulforaphane and erucin: characterization, metabolism, and interconversion. Mol Nutr Food Res. 2012;56(11):1675–87.PubMedCrossRefGoogle Scholar
  58. 58.
    Choi S, Singh SV. Bax and Bak are required for apoptosis induction by sulforaphane, a cruciferous vegetable-derived cancer chemopreventive agent. Cancer Res. 2005;65(5):2035–43.PubMedCrossRefGoogle Scholar
  59. 59.
    Bhattacharya A, Li Y, Shi Y, Zhang Y. Enhanced inhibition of urinary bladder cancer growth and muscle invasion by allyl isothiocyanate and celecoxib in combination. Carcinogenesis. 2013;34(11):2593–9.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Lee YM, Cho HJ, Ponnuraj SP, Kim J, Kim JS, Kim SG, et al. Phenethyl isothiocyanate inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammatory responses in mouse skin. J Med Food. 2011;14(4):377–85.PubMedCrossRefGoogle Scholar
  61. 61.
    Shan Y, Wu K, Wang W, Wang S, Lin N, Zhao R, et al. Sulforaphane down-regulates COX-2 expression by activating p38 and inhibiting NF-kappaB-DNA-binding activity in human bladder T24 cells. Int J Oncol. 2009;34(4):1129–34.PubMedGoogle Scholar
  62. 62.
    Tang L, Zhang Y. Dietary isothiocyanates inhibit the growth of human bladder carcinoma cells. J Nutr. 2004;134(8):2004–10.PubMedCrossRefGoogle Scholar
  63. 63.
    Mukherjee P, Winter SL, Alexandrow MG. Cell cycle arrest by transforming growth factor beta1 near G1/S is mediated by acute abrogation of prereplication complex activation involving an Rb-MCM interaction. Mol Cell Biol. 2010;30(3):845–56.PubMedCrossRefGoogle Scholar
  64. 64.
    Tong YH, Zhang B, Fan Y, Lin NM. Keap1-Nrf2 pathway: a promising target towards lung cancer prevention and therapeutics. Chronic Dis Transl Med. 2015;1(3):175–86.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Bricker GV, Riedl KM, Ralston RA, Tober KL, Oberyszyn TM, Schwartz SJ. Isothiocyanate metabolism, distribution, and interconversion in mice following consumption of thermally processed broccoli sprouts or purified sulforaphane. Mol Nutr Food Res. 2014;58(10):1991–2000.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Munday R, Munday CM. Induction of phase II detoxification enzymes in rats by plant-derived isothiocyanates: comparison of allyl isothiocyanate with sulforaphane and related compounds. J Agric Food Chem. 2004;52(7):1867–71.PubMedCrossRefGoogle Scholar
  67. 67.
    • Alumkal JJ, Slottke R, Schwartzman J, Cherala G, Munar M, Graff JN, et al. A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer. Invest New Drugs. 2015;33(2):480–9 Based on results of their work demonstrating that sulforaphane inhibits AR signaling in prostate cancer cells, the current study reports results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. The study was the first to report the safety of treatment and the effects of sulforaphane extract on PSA doubling time modulation. These are critical data of safety that inform future development of early-phase clinical trials in humans. PubMedCrossRefGoogle Scholar
  68. 68.
    • Atwell LL, Hsu A, Wong CP, Stevens JF, Bella D, Yu TW, et al. Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract. Mol Nutr Food Res. 2015;59(3):424–33 These are critical data of bioavailability that inform future development of early-phase clinical trials in humans. PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    • Cipolla BG, Mandron E, Lefort JM, Coadou Y, Della Negra E, Corbel L, et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer Prev Res (Phila). 2015;8(8):712–9 The current study was the first randomized clinical trials to report that daily administration of free sulforaphane shows promise in managing biochemical recurrences in prostate cancer after radical prostatectomy. These are critical data of safety and efficacy that inform future development of early-phase clinical trials in humans. CrossRefGoogle Scholar
  70. 70.
    Traka M, Gasper AV, Melchini A, Bacon JR, Needs PW, Frost V, et al. Broccoli consumption interacts with GSTM1 to perturb oncogenic signalling pathways in the prostate. PLoS One. 2008;3(7):e2568.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Egner PA, Chen JG, Wang JB, Wu Y, Sun Y, Lu JH, et al. Bioavailability of Sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. Cancer Prev Res (Phila). 2011;4(3):384–95.CrossRefGoogle Scholar
  72. 72.
    Ye L, Dinkova-Kostova AT, Wade KL, Zhang Y, Shapiro TA, Talalay P. Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta. 2002;316(1–2):43–53.PubMedCrossRefGoogle Scholar
  73. 73.
    Bryan RT, Zeegers MP, James ND, Wallace DM, Cheng KK. Biomarkers in bladder cancer. BJU Int. 2010;105(5):608–13.PubMedCrossRefGoogle Scholar
  74. 74.
    Gonzalez-Campora R, Davalos-Casanova G, Beato-Moreno A, Luque RJ, Alvarez-Kindelan J, Requena MJ, et al. Apoptotic and proliferation indexes in primary superficial bladder tumors. Cancer Lett. 2006;242(2):266–72.PubMedCrossRefGoogle Scholar
  75. 75.
    Ding W, Gou Y, Sun C, Xia G, Wang H, Chen Z, et al. Ki-67 is an independent indicator in non-muscle invasive bladder cancer (NMIBC); combination of EORTC risk scores and Ki-67 expression could improve the risk stratification of NMIBC. Urol Oncol. 2014;32(1):42 e13–9.CrossRefGoogle Scholar
  76. 76.
    Gasper AV, Al-Janobi A, Smith JA, Bacon JR, Fortun P, Atherton C, et al. Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. Am J Clin Nutr. 2005;82(6):1283–91.PubMedCrossRefGoogle Scholar
  77. 77.
    Islam SS, Mokhtari RB, Akbari P, Hatina J, Yeger H, Farhat WA. Simultaneous targeting of bladder tumor growth, survival, and epithelial-to-mesenchymal transition with a novel therapeutic combination of acetazolamide (AZ) and sulforaphane (SFN). Target Oncol. 2016;11(2):209–27.PubMedCrossRefGoogle Scholar
  78. 78.
    Santos LL, Amaro T, Pereira SA, Lameiras CR, Lopes P, Bento MJ, et al. Expression of cell-cycle regulatory proteins and their prognostic value in superficial low-grade urothelial cell carcinoma of the bladder. Eur J Surg Oncol. 2003;29(1):74–80.PubMedCrossRefGoogle Scholar
  79. 79.
    Mukherjee P, Cao TV, Winter SL, Alexandrow MG. Mammalian MCM loading in late-G(1) coincides with Rb hyperphosphorylation and the transition to post-transcriptional control of progression into S-phase. PLoS One. 2009;4(5):e5462.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Mackenzie GG, Queisser N, Wolfson ML, Fraga CG, Adamo AM, Oteiza PI. Curcumin induces cell-arrest and apoptosis in association with the inhibition of constitutively active NF-kappaB and STAT3 pathways in Hodgkin's lymphoma cells. Int J Cancer. 2008;123(1):56–65.PubMedCrossRefGoogle Scholar
  81. 81.
    Baker M. Deceptive curcumin offers cautionary tale for chemists. Nature News. 2017;541(7636):144–5.CrossRefGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  • Aniruddha Ganguly
    • 1
    Email author
  • David Frank
    • 2
  • Nagi Kumar
    • 3
  • Yung-Chi Cheng
    • 4
  • Edward Chu
    • 5
  1. 1.Cancer Diagnosis Program, Division of Cancer Treatment and DiagnosisNational Cancer Institute at the National Institutes of HealthRockvilleUSA
  2. 2.Dana Farber Cancer Institute and Harvard Medical SchoolBostonUSA
  3. 3.H. Lee Moffitt Cancer Center and Research InstituteUniversity of South FloridaTampaUSA
  4. 4.Department of Pharmacology, Developmental Therapeutics Program, Yale Cancer CenterYale University School of MedicineNew HavenUSA
  5. 5.Department of Medicine, Cancer Therapeutics Program, UPMC Hillman Cancer CenterUniversity of Pittsburgh School of MedicinePittsburghUSA

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