cancers Review Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence Antonella Di Sotto 1,* , Romina Mancinelli 2 , Marco Gullì 1, Margherita Eufemi 3 , Caterina Loredana Mammola 2 , Gabriela Mazzanti 1,* and Silvia Di Giacomo 1 1 Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy; [email protected] (M.G.); [email protected] (S.D.G.) 2 Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy; [email protected] (R.M.); [email protected] (C.L.M.) 3 Department of Biochemical Science “A. Rossi Fanelli”, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy; [email protected] * Correspondence: [email protected] (A.D.S.); [email protected] (G.M.); Tel.: +39-06-499-12497 (A.D.S.); +39-06-499-12903 (G.M.) Received: 7 September 2020; Accepted: 15 October 2020; Published: 18 October 2020 Simple Summary: Caryophyllane sesquiterpenes are unique natural compounds widely occurring in nature, especially in plant essential oils, that are characterized by multiple properties of pharmacological interest. Although β-caryophyllene is the most investigated compound, its metabolite β-caryophyllene oxide and the analogues α-humulene and isocaryophyllene have been evaluated, too. Previous studies showed a polypharmacological profile of these compounds and a possible interest in cancer research; however, emerging evidence have highlighted a complex pool of healing properties, including a block of carcinogen-mediated DNA damage and cytoprotection against anticancer drug toxicity in noncancerous cells, along with antiproliferative and chemosensitizing activitives in cancer cells, thus suggesting their promising role as chemopreventive agents. In line with this evidence, the present review provides the pharmacological basis to support a further therapeutic interest for caryophyllane sesquiterpenes as chemopreventive agents. Moreover, possible structure–activity relationships and future research directions have been highlighted. Abstract: Chemoprevention is referred to as a strategy to inhibit, suppress, or reverse tumor development and progression in healthy people along with high-risk subjects and oncologic patients through using pharmacological or natural substances. Numerous phytochemicals have been widely described in the literature to possess chemopreventive properties, although their clinical usefulness remains to be defined. Among them, caryophyllane sesquiterpenes are natural compounds widely occurring in nature kingdoms, especially in plants, fungi, and marine environments. Several structures, characterized by a common caryophyllane skeleton with further rearrangements, have been identified, but those isolated from plant essential oils, including β-caryophyllene, β-caryophyllene oxide, α-humulene, and isocaryophyllene, have attracted the greatest pharmacological attention. Emerging evidence has outlined a complex polypharmacological profile of caryophyllane sesquiterpenes characterized by blocking, suppressing, chemosensitizing, and cytoprotective properties, which suggests a possible usefulness of these natural substances in cancer chemoprevention for both preventive and adjuvant purposes. In the present review, the scientific knowledge about the chemopreventive properties of caryophyllane sesquiterpenes and the mechanisms involved have been collected and discussed; moreover, possible structure–activity relationships have been highlighted. Although further high-quality studies are required, the promising Cancers 2020, 12, 3034; doi:10.3390/cancers12103034 www.mdpi.com/journal/cancers CancersCancers 20202020,, 1122,, x 3034 FOR PEER REVIEW 2 2of of 49 48 quality studies are required, the promising preclinical findings and the safe pharmacological profile encouragepreclinical further findings studies and the tosafe define pharmacological a clinical usefulness profile of encourage caryophyllane further sesquiterpenes studies to define in primary, a clinical secondary,usefulness or of tertiary caryophyllane chemoprevention. sesquiterpenes in primary, secondary, or tertiary chemoprevention. Keywords:Keywords: ββ-caryophyll-caryophyllene;ene; ββ-caryophyllene-caryophyllene oxide; oxide; αα--humulene;humulene; isocaryophyllene; isocaryophyllene; apoptosis apoptosis;; membranemembrane permeability; permeability; ABC ABC transporters; transporters; genoprotection genoprotection;; STAT3 STAT3;; Nrf2 1.1. Introduction Introduction ChemopreventionChemoprevention is is defined defined as as the the us usee of of synthet syntheticic or or natural natural compounds compounds known known as as blocking blocking andand suppressing suppressing agents, agents, which which are are able able to to inhibit, inhibit, suppress suppress,, or or reverse reverse tumor tumor development development and and progressionprogression byby disruptingdisrupting multiple multiple pathways pathways and processesand processes during during carcinogenesis carcinogenesis stages (i.e., stages initiation, (i.e., initiation,promotion, promotion, and progression) and progression [1,2]. Blocking) [1,2]. Blocking agents are agents usually are e ffusuallyective duringeffective initiation, during initiation, inducing inducingcellular defenses cellular (i.e.,defenses detoxifying (i.e., detoxifying/antioxidant/antioxidant enzymes), enzymes protecting), protecting cells from cells oncogenic from expressiononcogenic expressionor acting throughor acting antimutagenic through antimutagenic and anti-inflammatory and anti-inflammatory mechanisms; mechanisms moreover,; moreover they can, they hinder can hinderthe carcinogen the carcinogen uptake uptake and bioactivation and bioactivation to electrophilic to electrophilic species, species, which which are responsible are responsible for DNA for DNAdamage damage [3–5]. [3 Suppressing–5]. Suppressing agents agents are able are to able stop to cancer stop developmentcancer development and progression and progression through throughdifferent different mechanisms, mechanisms, including alteredincluding gene altered expression gene and expression signaling cascades,and signaling the promotion cascades, of the cell promotsenescence,ion of an cell induction senescence, of cell an diinducfferentiationtion of cell or differentiation apoptosis, cell or cycle apoptosis, block, orcell by cycle the activationblock, or by of thetumor-suppressive activation of tumor signalings-suppressive [6,7]. signalings [6,7]. CancerCancer chemopreventionchemoprevention may may be usefullybe usefully exploited exploited not only throughnot only using through dietary phytochemicalsusing dietary phytochemicalsin healthy people in (primary healthy chemoprevention) people (primary butchemoprevention) also administering but suitable also administering pharmacological suitable agents pharmacologicalin high-risk subjects agents (secondary in high- chemoprevention)risk subjects (secondary in order chemoprevention) to prevent the progression in order ofto premalignant prevent the progressionlesions and of as premalignant adjuvant treatments lesions inand oncologic as adjuvant or post-treated treatments in patients oncologic (tertiary or post chemoprevention)-treated patients (tertiary(Figure1 chemoprevention))[ 6]. The latter agents (Figure are 1) defined [6]. The as latter chemosensitizers agents are defined and can as supportchemosensitizers chemotherapy and can by supportsynergistic chemotherapy or additive by eff synergisticects, thus increasing or additive the effects, effectiveness thus increasing of low-dose the effectiveness anticancer drugsof low- whiledose anticloweringancer thedrugs occurrence while lowering of intolerable the occurrence side effects. of Moreover, intolerable they side may effects restore. Moreover, the responsiveness they may of restorecancer tothe the responsiveness pharmacological of treatmentscancer to the and pharmacological improve the rate oftreatments relapse-free and survival improv ine post-treatedthe rate of relapsecancer- patientsfree survival by targeting in post specific-treated mechanisms cancer patients of chemoresistance, by targeting such spec as alterationsific mechanisms in drug fateof chemoresistance,(i.e., uptake, export such by as ATP-binding alterations in cassette drug fate (ABC) (i.e. transporters, uptake, export and by intracellular ATP-binding biotransformation), cassette (ABC) transportersimbalance between and intracellular pro-apoptotic biotransformation), and pro-survival imbalance factors, changes between in proteinpro-apoptotic expression, and andpro- defectivesurvival factors,DNA repair changes systems in protein [8,9]. expression, and defective DNA repair systems [8,9]. FigureFigure 1. 1. RoleRole of of c chemopreventionhemoprevention in in healthy healthy people people,, high high-risk-risk subjects subjects and and cancer cancer patients patients.. Cancers 2020, 12, 3034 3 of 48 In the last few years, there has been a growing interest in the identification of suitable chemopreventive (or cancer risk-reducing) agents not only to protect healthy people, but also as adjuvant regimens in oncologic and post-treated cancer patients. A number of drugs with off-target effects (namely repurposing drugs) along with phytochemicals have been approached as possible chemopreventive agents, but their efficacy has been found often null or controversial in clinical trials