Natural Withanolides in the Treatment of Chronic Diseases.
Withanolides, and in particular extracts from Withania somnifera, have been used for over 3,000 years in traditional Ayurvedic and Unani Indian medical systems as well as within several other Asian countries. Traditionally, the extracts were ascribed a wide range of pharmacologic properties with corresponding medical uses, including adaptogenic, diuretic, anti-inflammatory, sedative/anxiolytic, cytotoxic, antitussive, and immunomodulatory. Since the discovery of the archetype withaferin A in 1965, approximately 900 of these naturally occurring, polyoxygenated steroidal lactones with 28-carbon ergostane skeletons have been discovered across 24 diverse structural types. Subsequently, extensive pharmacologic research has identified multiple mechanisms of action across key inflammatory pathways. In this chapter we identify and describe the major withanolides with anti-inflammatory properties, illustrate their role within essential and supportive inflammatory pathways (including NF-κB, JAK/STAT, AP-1, PPARγ, Hsp90 Nrf2, and HIF-1), and then discuss the clinical application of these withanolides in inflammation-mediated chronic diseases (including arthritis, autoimmune, cancer, neurodegenerative, and neurobehavioral). These naturally derived compounds exhibit remarkable biologic activity across these complex disease processes, while showing minimal adverse effects. As novel compounds and analogs continue to be discovered, characterized, and clinically evaluated, the interest in withanolides as a novel therapeutic only continues to grow.
Department of Surgery, University of Michigan Hospital and Health Systems, 2920K Taubman Center, SPC 5331, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5331, USA.
Peter T
PT
White
Department of Surgery, University of Michigan Hospital and Health Systems, 2920K Taubman Center, SPC 5331, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5331, USA.
Chitra
C
Subramanian
Department of Surgery, University of Michigan Hospital and Health Systems, 2920K Taubman Center, SPC 5331, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5331, USA.
Hashim F
HF
Motiwala
Department of Surgery, University of Michigan Hospital and Health Systems, 2920K Taubman Center, SPC 5331, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5331, USA. cohenmar@med.umich.edu.
Mark S
MS
Cohen
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002908:Chronic Disease; D006801:Humans; D016328:NF-kappa B / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy; D009422:Nervous System Diseases / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D054358:Withanolides / Q000494:pharmacology / Q000627:therapeutic use*
D016328:NF-kappa B; D054358:Withanolides
Autoimmune; Cancer; Inflammation; NF-κB; Neurodegenerative; Withaferin A; Withanolide
Oncol Rep. 2013 Aug;30(2):933-8
23708780
Ann Rheum Dis. 2011 Mar;70 Suppl 1:i109-12
21339212
Mol Carcinog. 2016 Nov;55(11):1739-1746
26472150
Pure Appl Chem. 2012;84(6):1353-1367
24098060
J Nat Prod. 2007 Jul;70(7):1146-52
17580910
Front Immunol. 2015 Oct 28;6:550
26579125
Hum Exp Toxicol. 2005 Mar;24(3):137-47
15901053
Int J Obes (Lond). 2014 Nov;38(11):1432-9
24566854
Cardiovasc Res. 2001 Feb 16;49(3):507-21
11166264
Phytother Res. 2008 Oct;22(10):1342-8
18697233
Am J Surg. 2012 Dec;204(6):895-900; discussion 900-1
23231932
Cardiovasc Toxicol. 2006;6(2):111-30
17303919
Appl Biochem Biotechnol. 2011 Oct;165(3-4):1075-91
21789568
Life Sci. 2003 Nov 21;74(1):125-32
14575818
Exp Biol Med (Maywood). 2003 Feb;228(2):111-33
12563018
Pharmacol Biochem Behav. 2003 Jun;75(3):547-55
12895672
J Med Food. 2009 Jun;12(3):591-600
19627208
Ann N Y Acad Sci. 2003 Jun;991:189-98
12846987
Nat Rev Drug Discov. 2006 Jul;5(7):549-63
16773072
Phytomedicine. 2014 Mar 15;21(4):406-14
24252344
Chem Biodivers. 2009 Sep;6(9):1415-26
19774603
Clin Cancer Res. 2009 Jan 15;15(2):425-30
19147746
Clin Neurophysiol. 2008 Jul;119(7):1459-74
18467168
Biol Psychiatry. 2008 Apr 15;63(8):801-8
18005941
Curr Clin Pharmacol. 2009 Sep;4(3):198-219
19500070
Cell Mol Biol Lett. 2007;12(4):473-81
17415533
Mol Cancer Ther. 2006 Jun;5(6):1434-45
16818501
J Complement Integr Med. 2015 Jun;12(2):117-25
25803089
Chem Biodivers. 2004 Sep;1(9):1289-95
17191906
Chem Pharm Bull (Tokyo). 2012;60(12):1494-501
23207631
BMC Bioinformatics. 2011 Feb 15;12 Suppl 1:S30
21342561
Mol Neurobiol. 2016 Aug;53(6):4143-4158
26208698
J Biol Chem. 2008 May 23;283(21):14665-73
18353781
Mol Pharmacol. 2007 Feb;71(2):426-37
17093135
Ann Rheum Dis. 2011 May;70(5):844-50
21173018
J Biosci. 2007 Mar;32(2):299-307
17435322
Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a000141
20066113
J Biol Chem. 2008 Jun 20;283(25):17184-93
18442981
Chem Biol Interact. 2006 Dec 15;164(3):174-80
17084827
Drug Des Devel Ther. 2011 Apr 06;5:185-210
21552489
PLoS One. 2012;7(7):e42265
22860102
ScientificWorldJournal. 2014;2014:780616
24995360
Cell Mol Life Sci. 2015 Dec;72(23):4445-60
26306935
Ann Ist Super Sanita. 2007;43(4):394-405
18209273
Mol Cancer. 2010 May 03;9:99
20438634
J Cancer Prev. 2015 Sep;20(3):185-92
26473157
J Nat Prod. 2010 May 28;73(5):966-8
20438092
In Silico Pharmacol. 2013 Jul 29;1:11
25505656
Biochem Soc Trans. 2015 Aug;43(4):687-9
26551713
Immunology. 2014 Mar;141(3):287-91
23758741
Science. 1997 Sep 12;277(5332):1630-5
9287210
PLoS One. 2013 Sep 12;8(9):e75069
24069380
PLoS One. 2014 Apr 16;9(4):e94803
24739900
J Med Chem. 2014 Apr 10;57(7):2851-63
24625088
J Nat Prod. 2015 Oct 23;78(10):2488-93
26492982
Inflammopharmacology. 2012 Aug;20(4):195-205
22160928
Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3510-5
22308347
Arthritis Res Ther. 2004;6(6):265-78
15535839
ScientificWorldJournal. 2014 Mar 16;2014:273870
24757415
Trends Immunol. 2004 Jun;25(6):280-8
15145317
Toxicol Appl Pharmacol. 2012 Jul 1;262(1):91-8
22561332
Recent Prog Horm Res. 2003;58:95-130
12795416
Pharm Biol. 2014 Mar;52(3):308-20
24188460
Phytochemistry. 2008 Feb;69(4):982-7
18086481
J Clin Psychiatry. 2009 Aug;70(8):1078-90
19497250
ACS Med Chem Lett. 2013 Nov 14;4(11):
24273633
Neurosci Res. 2004 Sep;50(1):67-75
15288500
Oncogene. 2006 Oct 30;25(51):6680-4
17072321
Immunology. 2014 Jun;142(2):151-66
24329535
Toxins (Basel). 2010 Oct;2(10):2428-66
22069560
J Exp Med. 1999 Jan 4;189(1):63-73
9874564
Exp Cell Res. 2013 Nov 1;319(18):2822-34
24016823
Int Immunopharmacol. 2011 Aug;11(8):1137-42
21396905
J Nat Prod. 2010 Jul 23;73(7):1196-202
20553006
J Biol Chem. 2007 Feb 16;282(7):4253-64
17150968
Chem Pharm Bull (Tokyo). 2004 Nov;52(11):1358-61
15520512
PLoS One. 2012;7(5):e37080
22606332
Indian J Exp Biol. 2008 Jun;46(6):470-5
18697607
PLoS One. 2010 Oct 21;5(10):e13536
20975835
Autoimmun Rev. 2015 Nov;14(11):1048-56
26226414
Trends Immunol. 2015 Jun;36(6):364-73
26001312
FEBS J. 2006 Dec;273(24):5714-23
17212786
Phytother Res. 2009 Jul;23(7):987-92
19152372
Mol Carcinog. 2015 Jun;54(6):417-29
24293234
Phytomedicine. 2000 Dec;7(6):463-9
11194174
Int Immunopharmacol. 2006 Sep;6(9):1394-403
16846833
AAPS J. 2014 Jan;16(1):1-10
24046237
Eur J Neurosci. 2006 Mar;23(6):1417-26
16553605
Gynecol Oncol. 2012 Mar;124(3):606-12
22188785
Indian J Exp Biol. 1997 Mar;35(3):236-9
9332168
Nat Prod Rep. 1991 Aug;8(4):415-40
1787922
Toxicol Appl Pharmacol. 2015 Dec 1;289(2):297-312
26408225
Breast Cancer Res Treat. 2012 Nov;136(1):45-56
22965833
Apoptosis. 2008 Dec;13(12):1450-64
18987975
Surgery. 2016 Jan;159(1):142-51
26542767
Steroids. 2014 Sep;87:26-34
24844203
J Clin Psychiatry. 2013 Nov;74(11):1076-83
24330893
PLoS One. 2015 Jul 31;10(7):e0134137
26230090
Nat Rev Cancer. 2009 Nov;9(11):798-809
19851315
Indian J Psychiatry. 2000 Jul;42(3):295-301
21407960
J Clin Rheumatol. 2004 Oct;10(5):236-45
17043520
PLoS One. 2013 Oct 16;8(10):e77624
24147038
Planta Med. 1984 Apr;50(2):134-6
6548033
Biochem Pharmacol. 2010 Feb 15;79(4):542-51
19769945
J Biol Chem. 2014 Jan 17;289(3):1852-65
24297176
J Radiat Res. 2003 Mar;44(1):1-6
12841592
J Allergy Clin Immunol. 2011 Feb;127(2):303-12; quiz 313-4
21281862
Br J Cancer. 2014 Aug 26;111(5):894-902
24983364
J Neurol Sci. 2000 Jun 15;176(2):124-7
10930594
Oncogene. 2002 Mar 27;21(13):2000-8
11960372
Mol Immunol. 2006 Apr;43(11):1855-63
16375970
J Cell Sci. 2004 Dec 1;117(Pt 25):5965-73
15564374
World J Surg. 2014 Jun;38(6):1343-52
24763440
Nat Rev Cancer. 2002 Oct;2(10):740-9
12360277
ACS Med Chem Lett. 2013 Jun 06;4(8):730-5
24900739
Eur J Pharmacol. 2003 Jan 10;459(1):107-12
12505539
PLoS One. 2012;7(8):e41214
22912669
ISRN Biochem. 2012 Sep 01;2012:707586
25969759
Carcinogenesis. 2010 Nov;31(11):1991-8
20724373
PLoS One. 2012;7(5):e37764
22701533
Indian J Psychol Med. 2012 Jul;34(3):255-62
23439798
BMC Complement Altern Med. 2011 Apr 28;11:34
21527003
Planta Med. 1997 Feb;63(1):15-7
9063090
Integr Cancer Ther. 2013 Jul;12(4):312-22
23142798
Br J Pharmacol. 2005 Apr;144(7):961-71
15711595
Tumour Biol. 2012 Aug;33(4):1179-89
22477711
Carcinogenesis. 2011 Nov;32(11):1697-705
21859835
J Nat Prod. 2006 Dec;69(12):1790-2
17190461
Nutr Rev. 2007 Dec;65(12 Pt 2):S140-6
18240538
Acta Pharm Sin B. 2015 Sep;5(5):378-89
26579469
J Nat Prod. 2001 Jun;64(6):720-5
11421731
J Ethnopharmacol. 2015 Aug 2;171:264-72
26068424
Cell Death Dis. 2015 Feb 26;6:e1666
25719250
Phytother Res. 2007 Oct;21(10):905-13
17562568
Phytochemistry. 2002 Mar;59(6):635-41
11867095
J Nat Prod. 2002 May;65(5):677-80
12027740
Neural Plast. 2015;2015:381964
26266054
Pharmacognosy Res. 2014 Jan;6(1):12-8
24497737
Evid Based Complement Alternat Med. 2005 Mar;2(1):99-105
15841284
Enzymes. 2015;37:73-94
26298456
Tumour Biol. 2007;28(3):123-31
17510563
Cell Death Dis. 2014 Oct 23;5:e1484
25341038
Surgery. 2012 Dec;152(6):1238-47
23158190
PLoS One. 2009 Aug 31;4(8):e6628
19718255
Mol Cancer Ther. 2014 Dec;13(12):2930-40
25236891
J Nat Prod. 2013 Mar 22;76(3):445-9
23252848
Int Immunopharmacol. 2009 Sep;9(10):1137-44
19524704
Biochem Biophys Res Commun. 2012 Oct 12;427(1):24-9
22982675
Indian J Med Res. 1991 Aug;94:312-5
1660034
Invest New Drugs. 2013 Jun;31(3):545-57
23129310
Nat Prod Res. 2014;28(22):1941-51
24871278
J Pharm Pharmacol. 2015 Jul;67(7):879-99
25828061
Trends Immunol. 2006 Jan;27(1):24-31
16316783
FEBS J. 2016 Feb;283(3):413-24
26513405
Indian J Physiol Pharmacol. 2007 Oct-Dec;51(4):345-53
18476388
J Biol Chem. 2009 Jan 30;284(5):2746-54
19049961
J Nat Prod. 2008 Apr;71(4):642-6
18348534
Nat Rev Cancer. 2003 Nov;3(11):859-68
14668816
Mol Cancer Ther. 2010 Jan;9(1):202-10
20053782
J Nat Prod. 2000 Aug;63(8):1113-6
10978207
Cancer Prev Res (Phila). 2014 Jul;7(7):738-47
24824039
PLoS One. 2014 Oct 13;9(10):e105311
25310001
Neurosci Lett. 2009 Apr 17;454(1):11-5
19429045
Invest New Drugs. 2014 Aug;32(4):604-17
24718901
Int Immunopharmacol. 2006 Mar;6(3):408-14
16428076
Mol Cell Biol. 2009 Oct;29(20):5488-504
19687301
Neurochem Res. 2013 May;38(5):972-80
23430469
Surgery. 2010 Dec;148(6):1228-36; discussion 1236
21134556
Nat Rev Cancer. 2009 Aug;9(8):537-49
19629069
Evid Based Complement Alternat Med. 2010 Jun;7(2):177-87
18955307
Int J Cancer. 2011 Dec 1;129(11):2744-55
21538350
Invest Ophthalmol Vis Sci. 2006 Sep;47(9):4138-45
16936134
J Biomol Struct Dyn. 2012;29(4):651-62
22208270
Br J Pharmacol. 2013 Feb;168(4):903-19
22978525
PLoS One. 2012;7(9):e44419
22973447
J Nat Prod. 2011 Dec 27;74(12):2532-44
22098611
Indian J Exp Biol. 2007 Jun;45(6):524-8
17585686
Life Sci. 2007 Mar 27;80(16):1525-38
17336338
Curr Med Chem. 2012;19(18):2876-900
22519398
Phytother Res. 1999 Jun;13(4):275-91
10404532
Neurosci Biobehav Rev. 2011 Jan;35(3):804-17
20934453
Nat Prod Rep. 2011 Apr;28(4):705-40
21344104
Chem Biodivers. 2007 Mar;4(3):443-9
17372946
J Nat Prod. 2013 Oct 25;76(10):1902-8
24128077
Steroids. 2012 Apr;77(5):441-7
22197662
J Nat Prod. 2010 Sep 24;73(9):1476-81
20726569
Oxid Med Cell Longev. 2014;2014:201436
25295146
Int J Neurosci. 2011 Apr;121(4):181-90
21329473
Neuroscience. 1995 Aug;67(3):631-47
7675192
J Altern Complement Med. 2014 Dec;20(12):901-8
25405876
Nat Rev Cancer. 2004 Feb;4(2):97-105
14964307
Immunopharmacol Immunotoxicol. 2010 Mar;32(1):63-73
19678736
Phytomedicine. 2004 Jul;11(5):452-60
15330502
Cell. 2000 Jan 7;100(1):57-70
10647931
Int J Radiat Biol. 1996 Feb;69(2):193-7
8609455
J Pharmacol Sci. 2014;125(1):83-90
24748433
J Altern Complement Med. 2009 Apr;15(4):423-30
19388865
Psychiatry Res. 2015 Sep 30;229(1-2):37-48
26296951
Biofactors. 2008;33(2):137-48
19346589
BMC Complement Altern Med. 2011 Oct 06;11:84
21978374
Cancer Res. 2008 Sep 15;68(18):7661-9
18794155
PLoS One. 2010 Apr 16;5(4):e10105
20419128
Chem Pharm Bull (Tokyo). 2002 Jun;50(6):760-5
12045329
Indian J Physiol Pharmacol. 2006 Oct-Dec;50(4):409-15
17402272
Prog Chem Org Nat Prod. 2011;94:127-229
21833839
Int Immunopharmacol. 2010 Mar;10(3):290-7
19951747
Int J Cancer. 1971 Nov 15;8(3):487-96
5002873
Biochem Insights. 2014 Nov 09;7:1-13
25452693
Curr Psychiatry Rep. 2012 Jun;14(3):220-8
22477442
Nat Prod Res. 2007 Aug;21(10):877-83
17680497
PLoS One. 2014 Sep 29;9(9):e107596
25264898
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3801-4
9108058
J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S3-23
20176265
Eur J Pharmacol. 2008 Dec 3;599(1-3):11-7
18838070
J Exp Clin Cancer Res. 2002 Dec;21(4):585-90
12636106
Mol Carcinog. 2016 May;55(5):864-81
25969134
Sci Signal. 2011 Feb 15;4(160):ra9
21325207
Cancer Res. 2007 Jan 1;67(1):246-53
17185378
J Ethnopharmacol. 2009 Sep 25;125(3):369-73
19666100
Nat Rev Immunol. 2002 Oct;2(10):725-34
12360211
J Natl Cancer Inst. 2013 Aug 7;105(15):1111-22
23821767
Anticancer Res. 2014 Nov;34(11):6327-32
25368231
Nature. 2011 Jun 15;474(7351):307-17
21677747
Steroids. 2010 Apr;75(4-5):346-9
20116389
Oncogene. 2010 Feb 4;29(5):625-34
19946328
Arch Pharm (Weinheim). 2002 Jun;335(6):267-76
12210769
PLoS One. 2012;7(9):e44039
22962598
Cancer Res. 2008 Jan 15;68(2):589-96
18199556
Mol Cell Biol. 2002 Apr;22(8):2515-23
11909946
Curr Opin Pharmacol. 2013 Aug;13(4):646-53
23660374
Cell. 1997 Apr 18;89(2):239-50
9108479
Cancer Biol Ther. 2015;16(7):1088-98
26020511
J Ethnopharmacol. 2006 Aug 11;107(1):107-15
16603328
Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
17183360
J Nat Prod. 2011 May 27;74(5):1132-41
21425785
Vascul Pharmacol. 2006 Jun;44(6):406-10
16713367
Biochem Soc Trans. 2015 Aug;43(4):611-20
26551701
Drug Discov Ther. 2011 Aug;5(4):195-201
22466301
Fundam Clin Pharmacol. 2007 Apr;21(2):157-64
17391288
Rheumatology (Oxford). 2000 Sep;39(9):1004-8
10986306
Adv Exp Med Biol. 2009;645:241-6
19227477
Angiogenesis. 2004;7(2):115-22
15516832
Neurochem Res. 2014 Dec;39(12):2527-36
25403619
Asian Pac J Trop Med. 2012 May;5(5):380-4
22546655
Int J Biochem Cell Biol. 2006;38(7):1043-9
16423552
Int J Mol Med. 2015 Jan;35(1):247-52
25351115
Cancer Res. 2002 Jun 15;62(12):3351-5
12067972
Indian J Med Res. 2015 Jan;141(1):100-6
25857501