biomedicines Review Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives Tapan Behl 1,*, Aditi Sharma 2, Lalit Sharma 2, Aayush Sehgal 1, Gokhan Zengin 3, Roxana Brata 4, Ovidiu Fratila 4 and Simona Bungau 5,* 1 Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; [email protected] 2 School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh 173229, India; [email protected] (A.S.); [email protected] (L.S.) 3 Department of Biology, Faculty of Science, Selcuk University Campus, Konya 42250, Turkey; [email protected] 4 Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; [email protected] (R.B.); [email protected] (O.F.) 5 Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania * Correspondence: [email protected] (T.B.); [email protected] (S.B.); Tel.: +91-852-517-931 (T.B.); +40-726-776-588 (S.B.) Received: 20 November 2020; Accepted: 4 December 2020; Published: 6 December 2020 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. Keywords: Withaferin A; anticancer; autophagy; chaperone 1. Introduction Phytotherapy is the frequent therapeutic approach in complementary as well as in traditional medicine since time immemorial. It is utilized by 60% of the global population and has a vital role in the health care system due to ease of availability and reduced cost compared with synthetic compounds. The result of screening showed that many synthetic drugs are derived from natural origin, which is now extensively used in pharmacological therapies [1]. Considering the importance and bringing novel therapies into the market, the herbals have always been at the forefront of synthetic drugs with complex molecular diversity and biological function variation. Herbals are considered as natural chemical factories for manufacturing natural compounds with structural diversity. The secondary metabolites from plant origin have gained renewed Biomedicines 2020, 8, 571; doi:10.3390/biomedicines8120571 www.mdpi.com/journal/biomedicines Biomedicines 2020, 8, 571 2 of 24 Biomedicines 2020, 8, x FOR PEER REVIEW 2 of 23 attentionbecause they because directly they or indirectly directly interact or indirectly with mu interactltiple cell with components, multiple mainly cell components, lipids and proteins, mainly lipidsthereby and altering proteins, the functions thereby alteringof dysregulated the functions cells [2]. of The dysregulated evaluation cellsof the [2 phytopharmacological]. The evaluation of theeffect phytopharmacological of potential herbal drugs effect is ofessential potential for drug herbal discovery drugs is and essential development for drug [3–6] discovery. Despite and the developmentconsiderable application [3–6]. Despite of natural the considerable compounds application in drug development, of natural compounds it is assumed in drug that development, plant-based itsources is assumed are still that unexplored plant-based and sources can be are scrutini still unexploredzed for new and therapeutic can be scrutinized approaches for new in the therapeutic modern approachesera. Artemisia in theannua modern can reveal era. Artemisia the significance annua can of this reveal field the (Quinhaosu) significance ofderived this field artemisinin, (Quinhaosu) the derivedantimalarial artemisinin, drug known the antimalarial for its long drug history known in forChinese its long traditional history in medicine Chinese traditionalin the treatment medicine of infevers. the treatment The anti-hypertensive of fevers. The agent anti-hypertensive reserpine is us agented to reserpine remedy issnake used bite to remedyin Indian snake traditional bite in Indianmedicine traditional [7]. Today medicine medicinal [7]. Todayplants medicinalare evaluated plants and are explored evaluated due and to explored modern due technologies, to modern technologies,including screening including and screening functional and assays functional [8]. Ther assayse is an [8]. escalating There is an demand escalating for demandnovel therapies for novel to therapiestreat diseases. to treat There diseases. is a growing There is interest a growing in natu interestrally in extracted naturally herbal extracted constituents herbal constituents as targets for as targetspotential for treatment. potential treatment. InIn thethe AyurvedicAyurvedic andand UnaniUnani systems,systems, overover thethe lastlast 30003000 years,years, the genus Withania (family: Solanaceae)Solanaceae) has been used used indigenously indigenously [9]. [9]. The The dist distributionribution is isseen seen widely widely in the in the dry dry regions regions of the of thetropical tropical and andsubtropical subtropical areas, areas, extending extending from fromthe Canary the Canary Islands Islands to the toMediterranean the Mediterranean region, region, North NorthAfrica, Africa, and ending and ending in Southeast/Southwest in Southeast/Southwest Asia. Asia. Its Itsnumerous numerous therapeutic therapeutic usages usages have have gained modernmodern scientificscientific attentionattention and emergedemerged inin WorldWorld HealthHealth OrganizationOrganization (WHO)(WHO) monographsmonographs onon preferredpreferred medicinal plants. WithaniaWithania Somnifera Somnifera (Ashwagandha)(Ashwagandha) belongs belongs to to the the family family Solanaceae. Solanaceae. It Ithas has local local names names like like asgandh, asgandh, punir punir (Hindi), (Hindi), Ghodakun, Ghodakun, Ghoda Ghoda (Gujrati), (Gujrati), Ashwagandha (Bengali), amukkura,amukkura, amkulangamkulang (Tamil),(Tamil), PulivendramPulivendram (Telugu),(Telugu), etc.etc. InIn Sanskrit,Sanskrit, AshwagandhaAshwagandha meansmeans “horse’s“horse’s smell”smell” probablyprobably arisesarises fromfrom thethe smellsmell ofof itsits root,root, bearbear aa resemblanceresemblance toto thatthat ofof aa sweatysweaty horse.horse. WSWS isis alsoalso known commonly as as Indian Indian ginseng ginseng and and Indian Indian winter winter cherry. cherry. In In Latin, Latin, somniferasomnifera is isknown known as as“sleep “sleep making,” making,” which which means means sedating sedating properties, properties, but itbut has itadaptogenic has adaptogenic properties properties or sexual or vitality sexual vitalitystrength strength [3]. Ashwagandha [3]. Ashwagandha roots rootsare constituted are constituted in numerous in numerous Ayurvedic, Ayurvedic, Siddha, Siddha, and and UnaniUnani formulationsformulations [[9].9]. ThisThis medicinalmedicinal plant’s plant’s therapeutic therapeu applicationstic applications include antidiabetic,include antidiabetic, anti-epileptic, anti-epileptic, anti-inflammatory, anti- anti-depressant,inflammatory, anti-depressant, anti-arthritic, anticoagulant,anti-arthritic, anti antipyreticcoagulant, antioxidant, antipyretic analgesic,antioxidant, regenerating, analgesic, rejuvenating,regenerating, andrejuvenating, promoting growthand promoting [10,11]. Thegrowth primary [10,11]. chemical The constituentsprimary chemical include compoundsconstituents ofinclude varying compounds chemical structuresof varying viz. chemical flavonoids, structures withanolides, viz. flavonoids, tannin, withanolides, and alkaloids. tannin, Of these, and withanolidesalkaloids. Of these, have steroidalwithanolides lactone have triterpenoids steroidal lactone at C28 triterpenoids position assembled at C28 position on a reorganizedassembled on or a integralreorganized ergostane or integral framework, ergostane of which framework, C22 and of C26 which are inC22 oxidized and C26 form are resulting in oxidized in the form lactone resulting ring (six-membered)in the lactone ring [11 (six-membered)]. [11]. ReverseReverse pharmacologypharmacology approaches approaches implicated implicated WA asWA a bioactive as a bioactive compound compound having the having maximum the pharmacologicalmaximum pharmacological potential of Ashwagandhapotential of Ashwagandha [12] (Figure1). The[12] analysis(Figure of1). the The WA analysis chemical of structure the WA displayedchemical structure 3