# Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives **Authors:** Tapan Behl, Aditi Sharma, Lalit Sharma, Aayush Sehgal, Gokhan Zengin, Roxana Brata, Ovidiu Fratila, Simona Bungau PMC · DOI: 10.3390/biomedicines8120571 · Biomedicines · 2020-12-06 ## TL;DR This paper reviews Withaferin A's potential as a natural compound for treating cancer and other diseases by targeting multiple biological pathways. ## Contribution The paper provides a comprehensive review of Withaferin A's therapeutic mechanisms and its applications across various diseases. ## Key findings - Withaferin A inhibits cancer progression by targeting oxidative stress, apoptosis, and cell proliferation. - It shows neuroprotective and cardioprotective effects through enzyme inhibition and AMPK activation. - Structural modifications of Withaferin A enhance its therapeutic outcomes in multiple diseases. ## Abstract Withaferin A (WA), a manifold studied, C28-steroidal lactone withanolide found in Withania somnifera. Given its unique beneficial effects, it has gathered attention in the era of modern science. Cancer, being considered a “hopeless case and the leading cause of death worldwide, and the available conventional therapies have many lacunae in the form of side effects. The poly pharmaceutical natural compound, WA treatment, displayed attenuation of various cancer hallmarks by altering oxidative stress, promoting apoptosis, and autophagy, inhibiting cell proliferation, reducing angiogenesis, and metastasis progression. The cellular proteins associated with antitumor pathways were also discussed. WA structural modifications attack multiple signal transduction pathways and enhance the therapeutic outcomes in various diseases. Moreover, it has shown validated pharmacological effects against multiple neurodegenerative diseases by inhibiting acetylcholesterinases and butyrylcholinesterases enzyme activity, antidiabetic activity by upregulating adiponectin and preventing the phosphorylation of peroxisome proliferator-activated receptors (PPARγ), cardioprotective activity by AMP-activated protein kinase (AMPK) activation and suppressing mitochondrial apoptosis. The current review is an extensive survey of various WA associated disease targets, its pharmacokinetics, synergistic combination, modifications, and biological activities. ## Linked entities - **Chemicals:** Withaferin A (PubChem CID 265237), doxorubicin (PubChem CID 31703) - **Diseases:** cancer (MONDO:0004992), diabetes (MONDO:0005015) - **Species:** Withania somnifera (taxon 126910) ## Full-text entities - **Genes:** CPT1A (carnitine palmitoyltransferase 1A) [NCBI Gene 1374] {aka CPT I, CPT1, CPT1-L, CPTI-L, L-CPT1}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, PPM1B (protein phosphatase, Mg2+/Mn2+ dependent 1B) [NCBI Gene 5495] {aka PP2C-beta, PP2C-beta-X, PP2CB, PP2CBETA, PPC2BETAX}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, RAB24 (RAB24, member RAS oncogene family) [NCBI Gene 53917], Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, PSMA2 (proteasome 20S subunit alpha 2) [NCBI Gene 5683] {aka HC3, MU, PMSA2, PSC2}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, F2 (coagulation factor II, thrombin) [NCBI Gene 2147] {aka PT, RPRGL2, THPH1}, FKBP4 (FKBP prolyl isomerase 4) [NCBI Gene 2288] {aka FKBP51, FKBP52, FKBP59, HBI, Hsp56, PPIase}, Raf1 (Raf1 proto-oncogene, serine/threonine kinase) [NCBI Gene 110157] {aka 6430402F14Rik, Craf1, D830050J10Rik, Raf-1, c-Raf, cRaf}, Terf2 (telomeric repeat binding factor 2) [NCBI Gene 21750] {aka TRF2}, Parp1 (poly (ADP-ribose) polymerase family, member 1) [NCBI Gene 11545] {aka 5830444G22Rik, ARTD1, Adprp, Adprt1, PARP, PPOL}, SNCA (synuclein alpha) [NCBI Gene 6622] {aka NACP, PARK1, PARK4, PD1}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, CFLAR (CASP8 and FADD like apoptosis regulator) [NCBI Gene 8837] {aka CASH, CASP8AP1, CLARP, Casper, FLAME, FLAME-1}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, TMPRSS2 (transmembrane serine protease 2) [NCBI Gene 7113] {aka PRSS10}, RHO (rhodopsin) [NCBI Gene 6010] {aka CSNBAD1, OPN2, RP4}, Kit (Kit proto-oncogene receptor tyrosine kinase) [NCBI Gene 16590] {aka Bs, CD117, Fdc, Gsfsco1, Gsfsco5, Gsfsow3}, RELA (RELA proto-oncogene, NF-kB subunit) [NCBI Gene 5970] {aka AIF3BL3, CMCU, NFKB3, p65}, NOTCH1 (notch receptor 1) [NCBI Gene 4851] {aka AOS5, AOVD1, TAN1, hN1}, Mpro [NCBI Gene 8673700], TNFRSF11B (TNF receptor superfamily member 11b) [NCBI Gene 4982] {aka OCIF, OPG, PDB5, TR1}, SMAD2 (SMAD family member 2) [NCBI Gene 4087] {aka CHTD8, JV18, JV18-1, LDS6, MADH2, MADR2}, BAX (BCL2 associated X, apoptosis regulator) [NCBI Gene 581] {aka BCL2L4}, ANXA2 (annexin A2) [NCBI Gene 302] {aka ANX2, ANX2L4, CAL1H, HEL-S-270, LIP2, LPC2}, IDE (insulin degrading enzyme) [NCBI Gene 3416] {aka INSULYSIN}, Ctnnb1 (catenin beta 1) [NCBI Gene 12387] {aka Bfc, Catnb, Mesc}, ACLY (ATP citrate lyase) [NCBI Gene 47] {aka ACL, ATPCL, CLATP}, Pparg (peroxisome proliferator activated receptor gamma) [NCBI Gene 19016] {aka Nr1c3, PPAR-gamma, PPAR-gamma2, PPARgamma, PPARgamma2}, Slc2a4 (solute carrier family 2 (facilitated glucose transporter), member 4) [NCBI Gene 20528] {aka GT2, Glut-4, Glut4, twgy}, PLAT (plasminogen activator, tissue type) [NCBI Gene 5327] {aka T-PA, TPA}, NQO1 (NAD(P)H quinone dehydrogenase 1) [NCBI Gene 1728] {aka DHQU, DIA4, DTD, NMOR1, NMORI, QR1}, TOMM22 (translocase of outer mitochondrial membrane 22) [NCBI Gene 56993] {aka 1C9-2, MST065, MSTP065, TOM22}, WAPL (WAPL cohesin release factor) [NCBI Gene 23063] {aka FOE, KIAA0261, WAPAL}, CYP19A1 (cytochrome P450 family 19 subfamily A member 1) [NCBI Gene 1588] {aka ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX}, Braf (B-Raf proto-oncogene, serine/threonine kinase) [NCBI Gene 109880] {aka 9930012E13Rik, B-raf, Braf-2, Braf2, C230098H17, D6Ertd631e}, SNAPIN (SNAP associated protein) [NCBI Gene 23557] {aka BLOC1S7, BLOS7, BORCS3, NEDBAC, SNAPAP}, IKBKG (inhibitor of nuclear factor kappa B kinase regulatory subunit gamma) [NCBI Gene 8517] {aka AMCBX1, EDAID1, FIP-3, FIP3, Fip3p, IKK-gamma}, PCNA (proliferating cell nuclear antigen) [NCBI Gene 5111] {aka ATLD2}, Cd24a (CD24a antigen) [NCBI Gene 12484] {aka Cd24, HSA, Ly-52, nectadrin}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, KEAP1 (kelch like ECH associated protein 1) [NCBI Gene 9817] {aka INrf2, KLHL19}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, MIA3 (MIA SH3 domain ER export factor 3) [NCBI Gene 375056] {aka D320, ODCD2, TANGO, TANGO1, UNQ6077}, Aldh1a1 (aldehyde dehydrogenase family 1, subfamily A1) [NCBI Gene 11668] {aka ALDH-E1, ALHDII, Ahd-2, Ahd2, Aldh1, Aldh1a2}, Irs1 (insulin receptor substrate 1) [NCBI Gene 16367] {aka G972R, IRS-1}, SRRT (serrate, RNA effector molecule) [NCBI Gene 51593] {aka ARS2, ASR2, serrate}, RUNX2 (RUNX family transcription factor 2) [NCBI Gene 860] {aka AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD}, Casp3 (caspase 3) [NCBI Gene 12367] {aka A830040C14Rik, AC-3, CASP-3, CC3, CPP-32, CPP32}, PRKCE (protein kinase C epsilon) [NCBI Gene 5581] {aka PKCE, nPKC-epsilon}, HSP90AA1 (heat shock protein 90 alpha family class A member 1) [NCBI Gene 3320] {aka EL52, HEL-S-65p, HSP86, HSP89A, HSP90A, HSP90N}, TTK (TTK protein kinase) [NCBI Gene 7272] {aka CT96, ESK, MPH1, MPS1, MPS1L1, PYT}, CCDC22 (CCC complex scaffolding subunit CCDC22) [NCBI Gene 28952] {aka CXorf37, JM1, RTSC2}, AGTR1 (angiotensin II receptor type 1) [NCBI Gene 185] {aka AG2S, AGTR1B, AT1, AT1AR, AT1B, AT1BR} - **Diseases:** MM (MESH:D009101), III (MESH:C537189), gastrointestinal tract (MESH:D005770), MI (MESH:D009203), bone erosion (MESH:D014077), prostate tumor (MESH:D011472), mesencephalic neuron injury (MESH:D020295), colorectal adenocarcinoma (MESH:D003110), HIV (MESH:D015658), NASH (MESH:D065626), diabetic complications (MESH:D048909), ALS (MESH:D008113), osteoporotic (MESH:D058866), Anti Hepatitis (MESH:D056486), Diabetes (MESH:D003920), weight loss (MESH:D015431), AD (MESH:D000544), intestinal polyp (MESH:D007417), metastatic (MESH:D000092182), neuroinflammation (MESH:D000090862), liver cirrhosis (MESH:D008103), Breast Cancer (MESH:D001943), cytotoxicity (MESH:D064420), hypertensive (MESH:D006973), death (MESH:D003643), AML (MESH:D015470), DNA (MESH:D004266), mitochondria (MESH:C564971), amyotrophic lateral sclerosis (MESH:D000690), edema (MESH:D004487), CLL (MESH:D015451), skeletal bone disorder (MESH:D001847), NSCLC (MESH:D002289), diastolic dysfunction (MESH:D018487), cognitive deficits (MESH:D003072), cardiovascular system disorders (MESH:D018376), sepsis (MESH:D018805), Cancer (MESH:D009369), neurotoxic (MESH:D020258), motor deficits (MESH:D009461), hyperglycemia (MESH:D006943), acute liver injury (MESH:D017114), osteosarcoma (MESH:D012516), platelet aggregation (MESH:D001791), COVID 19 (MESH:D000086382), mitochondrial apoptosis (MESH:D028361), tumorigenic (MESH:D002471), oral cancer (MESH:D009062), Insulin-dependent (MESH:D003922), Prostate Cancer (MESH:D011471), hypertrophic cardiomyopathy (MESH:D002312), Myocardial fibrosis (MESH:D005355), Lung Cancer (MESH:D008175), snake bite (MESH:D012909), cardiac disorders (MESH:D006331), PD (MESH:D010300), liver injury (MESH:D017093), neuroblastoma (MESH:D009447), hepatic steatosis (MESH:D005234), dementias (MESH:D003704) - **Chemicals:** fatty acids (MESH:D005227), glycolipids (MESH:D006017), ergostane (MESH:C015190), catecholamines (MESH:D002395), oxaliplatin (MESH:D000077150), PAC (MESH:D017239), Cisplatin (MESH:D002945), doxorubicin (MESH:D004317), nitrile (MESH:D009570), glucose (MESH:D005947), artemisinin (MESH:C031327), DOXIL (MESH:C506643), cysteine (MESH:D003545), DA (MESH:D004298), Dexamethasone (MESH:D003907), MY (MESH:C040015), 5-FU (MESH:D005472), free fatty acid (MESH:D005230), carbohydrates (MESH:D002241), N (MESH:D009584), caffeic acid phenethyl ester (MESH:C055494), WA (MESH:C009684), HVA (MESH:D006719), fucose (MESH:D005643), 3beta-methoxy-Withaferin-A (-), ceramides (MESH:D002518), TBARS (MESH:D017392), acetylcholine (MESH:D000109), cocaine (MESH:D003042), alkaloids (MESH:D000470), N-acetylcysteine (MESH:D000111), Polycaprolactone (MESH:C016240), 3-azido WA (MESH:C577558), adenosine triphosphate (MESH:D000255), 6-OHDA (MESH:D016627), acetate (MESH:D000085), calcium (MESH:D002118), 2,3-dihydro-3beta-methoxy Withaferin A (MESH:C000624641), glutathione (MESH:D005978), triterpenoids (MESH:D014315), acetaminophen (MESH:D000082), choline (MESH:D002794), withanolides (MESH:D054358), withanone (MESH:C560597), 1-methyl-4-phenylpyridinium (MESH:D015655), epoxide (MESH:D004852), lactone (MESH:D007783), ferric chloride (MESH:C024555), lipopeptide (MESH:D055666), lipid (MESH:D008055), free radicals (MESH:D005609), reserpine (MESH:D012110), flavonoids (MESH:D005419), STZ (MESH:D013311), rosiglitazone (MESH:D000077154), sialic acid (MESH:D019158), tannin (MESH:D013634), SO (MESH:D000077157), ROS (MESH:D017382) - **Species:** Cricetus cricetus (black-bellied hamster, species) [taxon 10034], Rattus norvegicus (brown rat, species) [taxon 10116], Artemisia annua (sweet Annie, species) [taxon 35608], Homo sapiens (human, species) [taxon 9606], Equus caballus (domestic horse, species) [taxon 9796], Mus musculus (house mouse, species) [taxon 10090], Withania somnifera (ashwagandha, species) [taxon 126910] - **Cell lines:** MCF-7 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0031), Caco-2 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0025), DU-145 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0105), BxPc-3 — Homo sapiens (Human), Pancreatic ductal adenocarcinoma, Cancer cell line (CVCL_0186), SUM159 — Homo sapiens (Human), Breast pleomorphic carcinoma, Cancer cell line (CVCL_5423), CaOV3 — Homo sapiens (Human), High grade ovarian serous adenocarcinoma, Cancer cell line (CVCL_0201), LNCaP — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0395), MiaPaCa2 — Homo sapiens (Human), Pancreatic undifferentiated carcinoma, Cancer cell line (CVCL_0428), Panc-1 — Homo sapiens (Human), Pancreatic ductal adenocarcinoma, Cancer cell line (CVCL_0480), A549 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_0023), TEP — Homo sapiens (Human), Chronic myelogenous leukemia, BCR-ABL1 positive, Cancer cell line (CVCL_TR95), H1299 — Homo sapiens (Human), Lung large cell carcinoma, Cancer cell line (CVCL_0060), N9 — Mus musculus (Mouse), Transformed cell line (CVCL_0452), HeLa — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_0030), PC-3 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0035), MDA-MB-231 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0062), HCT116 — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_0291), CP70 — Homo sapiens (Human), Ovarian endometrioid adenocarcinoma, Cancer cell line (CVCL_0135), SKOV3 — Homo sapiens (Human), Ovarian serous cystadenocarcinoma, Cancer cell line (CVCL_0532), EA.hy926 — Homo sapiens (Human), Hybrid cell line (CVCL_3901), SW480 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0546), A2780 — Homo sapiens (Human), Ovarian endometrioid adenocarcinoma, Cancer cell line (CVCL_0134), B16F1 — Mus musculus (Mouse), Mouse melanoma, Cancer cell line (CVCL_0158) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC7762146/full.md ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC7762146/full.md ## References 166 references — full list in the complete paper: https://tomesphere.com/paper/PMC7762146/full.md --- Source: https://tomesphere.com/paper/PMC7762146