Planta Med 2017; 83(09): 752-760
DOI: 10.1055/s-0043-109558
Reviews
Georg Thieme Verlag KG Stuttgart · New York

Targeting Multiple Myeloma Cancer Stem Cells with Natural Products – Lessons from Other Hematological Malignancies

Mark E. Issa
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Sylvian Cretton
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Muriel Cuendet
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

received 21 February 2017
revised 05 April 2017

accepted 17 April 2017

Publication Date:
04 May 2017 (online)

Abstract

Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow. Multiple myeloma is the second most frequently diagnosed hematological malignancy, predominantly affecting the elderly. Despite recent advances in the development of novel therapies, multiple myeloma remains an incurable malignancy where the majority of patients relapse, develop resistance, and eventually die from the disease. This has been attributed to the fact that conventional therapy currently in use targets mainly the bulk of tumor cells, but not the tumor-initiating cancer stem cells. Cancer stem cells are a highly resistant subpopulation of cells believed to be responsible for the initiation, progression, metastasis, and relapse of cancer. Enormous efforts have been invested in the characterization of cancer stem cells. These efforts led to the characterization of key cellular signaling pathways responsible for conferring stem cell characteristics including self-renewal, differentiation, migratory, survival, and intracellular detoxification capabilities. Targeting these protective mechanisms offers a valuable strategy that may help combat a major driving force behind cancers. The use of natural products offers a promising therapeutic approach for targeting cancer stem cells. In this review, recent advances achieved in the characterization of cancer stem cells derived from hematological malignancies, with a particular focus on multiple myeloma, are discussed and major natural products that target cancer stem cells are presented. As natural products remain an essential source of novel chemical structures and medicinal leads, the exploitation of this immense reservoir is used to draw lessons in targeting multiple myeloma-cancer stem cells.

 
  • References

  • 1 Agarwal JR, Matsui W. Multiple myeloma: a paradigm for translation of the cancer stem cell hypothesis. Anticancer Agents Med Chem 2010; 10: 116-120
  • 2 San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Gunther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Blade J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; 15: 1195-1206
  • 3 Rajkumar SV. Treatment of multiple myeloma. Nat Rev Clin Oncol 2011; 8: 479-491
  • 4 Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med 2007; 58: 267-284
  • 5 Subramaniam D, Ramalingam S, Houchen CW, Anant S. Cancer stem cells: a novel paradigm for cancer prevention and treatment. Mini Rev Med Chem 2010; 10: 359-371
  • 6 Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351: 1860-1873
  • 7 Drewinko B, Alexanian R, Boyer H, Barlogie B, Rubinow SI. The growth fraction of human myeloma cells. Blood 1981; 57: 333-338
  • 8 Huff CA, Matsui W. Multiple myeloma cancer stem cells. J Clin Oncol 2008; 26: 2895-2900
  • 9 Bergsagel DE, Valeriote FA. Growth characteristics of a mouse plasma cell tumor. Cancer Res 1968; 28: 2187-2196
  • 10 Hamburger A, Salmon SE. Primary bioassay of human myeloma stem cells. J Clin Invest 1977; 60: 846-854
  • 11 Basak GW, Carrier E. The search for multiple myeloma stem cells: the long and winding road. Biol Blood Marrow Transplant 2010; 16: 587-594
  • 12 Pilarski LM, Belch AR. Circulating monoclonal B cells expressing P glycoprotein may be a reservoir of multidrug-resistant disease in multiple myeloma. Blood 1994; 83: 724-736
  • 13 Pilarski LM, Hipperson G, Seeberger K, Pruski E, Coupland RW, Belch AR. Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice. Blood 2000; 95: 1056-1065
  • 14 Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, Smith BD, Civin CI, Jones RJ. Characterization of clonogenic multiple myeloma cells. Blood 2004; 103: 2332-2336
  • 15 Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer 2005; 5: 275-284
  • 16 Jakubikova J, Adamia S, Kost-Alimova M, Klippel S, Cervi D, Daley JF, Cholujova D, Kong SY, Leiba M, Blotta S, Ooi M, Delmore J, Laubach J, Richardson PG, Sedlak J, Anderson KC, Mitsiades CS. Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood 2011; 117: 4409-4419
  • 17 Hawley TS, Riz I, Yang W, Wakabayashi Y, Depalma L, Chang YT, Peng W, Zhu J, Hawley RG. Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1. Am J Hematol 2013; 88: 265-272
  • 18 Lin MG, Liu LP, Li CY, Zhang M, Chen Y, Qin J, Gu YY, Li Z, Wu XL, Mo SL. Scutellaria extract decreases the proportion of side population cells in a myeloma cell line by down-regulating the expression of ABCG2 protein. Asian Pac J Cancer Prev 2013; 14: 7179-7186
  • 19 Gu YY, Liu LP, Qin J, Zhang M, Chen Y, Wang D, Li Z, Tang JZ, Mo SL. Baicalein decreases side population proportion via inhibition of ABCG2 in multiple myeloma cell line RPMI 8226 in vitro . Fitoterapia 2014; 94: 21-28
  • 20 Fuchs D, Daniel V, Sadeghi M, Opelz G, Naujokat C. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells. Biochem Biophys Res Commun 2010; 394: 1098-1104
  • 21 Januchowski R, Wojtowicz K, Zabel M. The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother 2013; 67: 669-680
  • 22 Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1: 555-567
  • 23 Croker AK, Allan AL. Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44+ human breast cancer cells. Breast Cancer Res Treat 2012; 133: 75-87
  • 24 Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, Tamaki Y, Noguchi S. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 2009; 15: 4234-4241
  • 25 Reghunathan R, Bi C, Liu SC, Loong KT, Chung TH, Huang G, Chng WJ. Clonogenic multiple myeloma cells have shared stemness signature associated with patient survival. Oncotarget 2013; 4: 1230-1240
  • 26 Yang SM, Yasgar A, Miller B, Lal-Nag M, Brimacombe K, Hu X, Sun H, Wang A, Xu X, Nguyen K, Oppermann U, Ferrer M, Vasiliou V, Simeonov A, Jadhav A, Maloney DJ. Discovery of NCT-501, a potent and selective theophylline-based inhibitor of aldehyde dehydrogenase 1A1 (ALDH1A1). J Med Chem 2015; 58: 5967-5978
  • 27 Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasiliou V. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev 2012; 64: 520-539
  • 28 Lowe ED, Gao GY, Johnson LN, Keung WM. Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase. J Med Chem 2008; 51: 4482-4487
  • 29 Kikonyogo A, Abriola DP, Dryjanski M, Pietruszko R. Mechanism of inhibition of aldehyde dehydrogenase by citral, a retinoid antagonist. Eur J Biochem 1999; 262: 704-712
  • 30 Rekha GK, Sladek NE. Inhibition of human class 3 aldehyde dehydrogenase, and sensitization of tumor cells that express significant amounts of this enzyme to oxazaphosphorines, by the naturally occurring compound gossypol. Adv Exp Med Biol 1997; 414: 133-146
  • 31 Tottmar O, Lindberg P. Effects on rat liver acetaldehyde dehydrogenases in vitro and in vivo by coprine, the disulfiram-like constituent of Coprinus atramentarius . Acta Pharmacol Toxicol 1977; 40: 476-481
  • 32 Heydenreuter W, Kunold E, Sieber SA. Alkynol natural products target ALDH2 in cancer cells by irreversible binding to the active site. Chem Commun 2015; 51: 15784-15787
  • 33 Patlolla JM, Qian L, Biddick L, Zhang Y, Desai D, Amin S, Lightfoot S, Rao CV. β-Escin inhibits NNK-induced lung adenocarcinoma and ALDH1A1 and RhoA/Rock expression in A/J mice and growth of H460 human lung cancer cells. Cancer Prev Res 2013; 6: 1140-1149
  • 34 Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasiliou V. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev 2012; 64: 520-539
  • 35 Michelot D. Poisoning by Coprinus atramentarius . Nat Toxins 1992; 1: 73-80
  • 36 Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and hedgehog pathways. Nat Rev Clin Oncol 2011; 8: 97-106
  • 37 OʼBrien CA, Kreso A, Jamieson CH. Cancer stem cells and self-renewal. Clin Cancer Res 2010; 16: 3113-3120
  • 38 Duman-Scheel M, Weng L, Xin S, Du W. Hedgehog regulates cell growth and proliferation by inducing cyclin D and cyclin E. Nature 2002; 417: 299-304
  • 39 Agren M, Kogerman P, Kleman MI, Wessling M, Toftgard R. Expression of the PTCH1 tumor suppressor gene is regulated by alternative promoters and a single functional Gli-binding site. Gene 2004; 330: 101-114
  • 40 Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol 2011; 27: 513-537
  • 41 Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, Watkins DN, Matsui W. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A 2007; 104: 4048-4053
  • 42 Kobune M, Takimoto R, Murase K, Iyama S, Sato T, Kikuchi S, Kawano Y, Miyanishi K, Sato Y, Niitsu Y, Kato J. Drug resistance is dramatically restored by hedgehog inhibitors in CD34+ leukemic cells. Cancer Sci 2009; 100: 948-955
  • 43 Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A 2011; 108: 13253-13257
  • 44 Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 2010; 16: 2580-2590
  • 45 Wang Z, Ahmad A, Li Y, Azmi AS, Miele L, Sarkar FH. Targeting notch to eradicate pancreatic cancer stem cells for cancer therapy. Anticancer Res 2011; 31: 1105-1113
  • 46 Lin LC, Yeh CT, Kuo CC, Lee CM, Yen GC, Wang LS, Wu CH, Yang WC, Wu AT. Sulforaphane potentiates the efficacy of imatinib against chronic leukemia cancer stem cells through enhanced abrogation of Wnt/beta-catenin function. J Agric Food Chem 2012; 60: 7031-7039
  • 47 Munoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol Oncol 2012; 6: 620-636
  • 48 Al-Hussaini H, Subramanyam D, Reedijk M, Sridhar SS. Notch signaling pathway as a therapeutic target in breast cancer. Mol Cancer Ther 2011; 10: 9-15
  • 49 Boucher K, Parquet N, Widen R, Shain K, Baz R, Alsina M, Koomen J, Anasetti C, Dalton W, Perez LE. Stemness of B-cell progenitors in multiple myeloma bone marrow. Clin Cancer Res 2012; 18: 6155-6168
  • 50 Nefedova Y, Sullivan DM, Bolick SC, Dalton WS, Gabrilovich DI. Inhibition of notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood 2008; 111: 2220-2229
  • 51 Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 2006; 106: 2503-2513
  • 52 Subramaniam D, Ponnurangam S, Ramamoorthy P, Standing D, Battafarano RJ, Anant S, Sharma P. Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. PLoS One 2012; 7: e30590
  • 53 Kong T, Wang Y, Xiao L, Liao L. Curcumin inhibits cell survival and migration by suppression of Notch-1 activity in prostate cancer cells. Int J Urol Nephrol 2013; 1: 35-39
  • 54 Issa ME, Berndt S, Carpentier G, Pezzuto JM, Cuendet M. Bruceantin inhibits multiple myeloma cancer stem cell proliferation. Cancer Biol Ther 2016; 17: 966-975
  • 55 Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Zhu N, Araldi E, Hu W, Freund J, Abdel-Wahab O, Ibrahim S, Skokos D, Armstrong SA, Levine RL, Park CY, Aifantis I. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med 2013; 210: 301-319
  • 56 Brennan SK, Wang Q, Tressler R, Harley C, Go N, Bassett E, Huff CA, Jones RJ, Matsui W. Telomerase inhibition targets clonogenic multiple myeloma cells through telomere length-dependent and independent mechanisms. PLoS One 2010; 5: e12487
  • 57 Bruedigam C, Bagger FO, Heidel FH, Kuhn CP, Guignes S, Song A, Austin R, Vu T, Lee E, Riyat S. Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy. Cell Stem Cell 2014; 15: 775-790
  • 58 Atkinson DJ, Brimble MA. Isolation, biological activity, biosynthesis and synthetic studies towards the rubromycin family of natural products. Nat Prod Rep 2015; 32: 811-840
  • 59 Nakai R, Kakita S, Asai A, Chiba S, Akinaga S, Mizukami T, Yamashita Y. Chrolactomycin, a novel antitumor antibiotic produced by Streptomyces sp. J Antibiot 2001; 54: 836-839
  • 60 Kim MY, Vankayalapati H, Shin-Ya K, Wierzba K, Hurley LH. Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular G-quadruplex. J Am Chem Soc 2002; 124: 2098-2099
  • 61 Chen JLY, Sperry J, Ip NY, Brimble MA. Natural products targeting telomere maintenance. MedChemComm 2011; 2: 229-245
  • 62 Miyazaki T, Pan Y, Joshi K, Purohit D, Hu B, Demir H, Mazumder S, Okabe S, Yamori T, Viapiano M, Shin-ya K, Seimiya H, Nakano I. Telomestatin impairs glioma stem cell survival and growth through the disruption of telomeric G-quadruplex and inhibition of the proto-oncogene, c-Myb. Clin Cancer Res 2012; 18: 1268-1280
  • 63 Guo QL, Lin SS, You QD, Gu HY, Yu J, Zhao L, Qi Q, Liang F, Tan Z, Wang X. Inhibition of human telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma SMMC-7721 cells. Life Sci 2006; 78: 1238-1245
  • 64 Puccetti E, Ruthardt M. Acute promyelocytic leukemia: PML/RARalpha and the leukemic stem cell. Leukemia 2004; 18: 1169-1175
  • 65 Werner B, Gallagher RE, Paietta EM, Litzow MR, Tallman MS, Wiernik PH, Slack JL, Willman CL, Sun Z, Traulsen A, Dingli D. Dynamics of leukemia stem-like cell extinction in acute promyelocytic leukemia. Cancer Res 2014; 74: 5386-5396
  • 66 Campos B, Wan F, Farhadi M, Ernst A, Zeppernick F, Tagscherer KE, Ahmadi R, Lohr J, Dictus C, Gdynia G, Combs SE, Goidts V, Helmke BM, Eckstein V, Roth W, Beckhove P, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende C. Differentiation therapy exerts antitumor effects on stem-like glioma cells. Clin Cancer Res 2010; 16: 2715-2728
  • 67 Issa ME, Cuendet M. Withaferin A induces cell death and differentiation in multiple myeloma cancer stem cells. MedChemComm 2017; 8: 112-121
  • 68 Hecht M, Heider U, Kaiser M, Von Metzler I, Sterz J, Sezer O. Osteoblasts promote migration and invasion of myeloma cells through upregulation of matrix metalloproteinases, urokinase plasminogen activator, hepatocyte growth factor and activation of p38 MAPK. Br J Haematol 2007; 138: 446-458
  • 69 Qiang YW, Walsh K, Yao L, Kedei N, Blumberg PM, Rubin JS, Shaughnessy J, Rudikoff S. Wnts induce migration and invasion of myeloma plasma cells. Blood 2005; 106: 1786-1793
  • 70 Li H, Guo L, Jie S, Liu W, Zhu J, Du W, Fan L, Wang X, Fu B, Huang S. Berberine inhibits SDF-1-induced AML cells and leukemic stem cells migration via regulation of SDF-1 level in bone marrow stromal cells. Biomed Pharmacother 2008; 62: 573-578