Multifunctional pentacyclic triterpenoids as adjuvants in cancer chemotherapy: a review

Abstract

Chemotherapeutic agents are a mainstay in the treatment of cancer. However, the nonselectivity of cytotoxic anticancer agents results in multiorgan toxicities. Cancer chemotherapy is often associated with toxicities, which can be expensive to manage and may affect the patient quality of life. Very few organ-protective agents like amifostine are proved as adjuvants to cancer chemotherapy. Amifostine protects against a wide range of chemo- and radiotherapy-related toxicities and reduces costs of supportive care. Multifunctional natural compounds like pentacyclic triterpenoids and their semisynthetic derivatives possess organ-protective activities against drug-induced toxicities. Triterpenoids interact with biomolecules involved in the cytotoxicity of chemotherapeutic agents. They also sensitize cancer cells for cytotoxic effect of chemotherapy. Further, pentacyclic triterpenoids themselves possess anticancer activity. The efficacy of pentacyclic triterpenoids as organotropic, anticancer and chemo sensitizers may prove these agents as adjuvant to cancer chemotherapy. The current review focuses on the systematic studies of the multifunctional role of pentacyclic triterpenoids and their derivatives in chemotherapy. Interactions of pentacyclic triterpenoids with molecular targets like nuclear factor erythroid-derived 2-like 2 (NrF2), nuclear factor kappa B (NFκ-B), protein kinase C (PKC), free radical scavenging, and cell longevity pathways that contribute to cytoprotective, anticancer, chemosensitizer and chemopreventive effects have been emphasized. The therapeutic utility of pentacyclic triterpenoids as multifunctional adjuvants in cancer chemotherapy is highlighted.

---

1. Introduction

Chemotherapeutic agents used in the treatment of cancer exert dose-dependent severe multiorgan toxicities.^1–3 An approach of targeted treatment with monoclonal antibodies is an emerging trend in cancer therapy that promises reduced organ toxicities. However, these targeted therapies have their own immune-related side effect and other disadvantages, including high cost.^4,5 Further, novel site-specific antibody–drug conjugate-based treatment is under clinical investigation.⁶ Even this mode of treatment is marred with other imitations in terms of site-specific delivery of chemotherapeutic agent and formulation-related problems. Hence, use of traditional cytotoxic drugs continues to be a preferred mode for the treatment of cancer.

To minimize the multiorgan toxicities of cancer chemotherapy, organ-protective adjuvants are also prescribed. Organ protectants are under clinical investigation, and a few drugs including amifostine are FDA adjuvants to cancer chemotherapy. Drugs like amifostine,⁷ alpha-lipoic acid,⁸ dexerazoxon, mesna, leucovorin, GM-CSF, recombinant erythropoietin, thrombopoietin,⁹ imidazenil¹⁰ and KR-22335 (ref. 11) are used as organ-protective adjuvants to cancer chemotherapy. Clinical and preclinical studies are having projected selenium, with and without vitamins as dietary adjuvants;^12,13 moreover, many natural bioactive agents are also able to restore the microstructure from hazardous chemical.¹⁴ However, shortcomings of currently available adjuvants in terms of pharmacoeconomics, short-term efficacy, and innate adverse effects limit their use. It is expected that adjuvants should not interfere with the cytotoxic effect of chemotherapy against cancer cells. To suffice such demands, there is a need for ideal organ-protective agents that do not interfere with the expected effects of chemotherapy without producing cumulative or irreversible toxicity. Further, such agent should provide effective long-term protection, should be easily administrable and should have an acceptable shelf life.¹⁵ These agents selectively protect the normal body cells from toxicities of chemotherapy with or without antagonizing the anticancer efficacy of chemotherapy. The currently used organ protectants are not devoid of innate toxicities. Thus, there is a need of an ideal, cost-effective, safe adjuvant to cancer chemotherapy that can protect normal body cells from cytotoxic actions and sensitize the cancer cell to chemotherapeutic agent. Apart from synthetic agent, naturally occurring agents may prove to be better adjuvants to cancer therapy.^16–18

Pentacyclic triterpenoids, widely distributed in the plant kingdom, have been extensively reported to possess protective effects against drug-induced organ toxicities including those of chemotherapeutic agents (Table 1). These agents exert a plethora of effects by interacting with multiple biomolecules. Their easy availability and routine consumption across the world's population point towards their safety. Hence, pentacyclic triterpenoids and their semisynthetic and/synthetic derivatives can be projected as organ-protective adjuvants to chemotherapy.^39,40

Table 1 Biological sources, chemical structures and parts of plants from which important pentacyclic triterpenoids are extracted

S. no.	Name of tritepenoid	Structure of triterpenoid	Source	Parts used for extraction	References
1	Betulinic acid		Vitex negundo (L.)	Leaves of Vitex negundo (L.)	19
2	Boswellic acid		Boswellia serrata	Gum resins of Boswellia serrata	20
3	Arjunolic acid		Terminalia arjuna	Bark	21
4	Maslinic acid		Orujo olive oil	Oil	22
5	Madecassic acid		Centella asiatica (L.)	Essential oil of Centella asiatica (L.)	23
6	Celastrol		Celastrus orbiculatus	Root of god thunder vine (Celastrus orbiculatus)	24 and 25
7	Pristimerin		Celastrus hypoleucus	Roots of Celastrus hypoleucus	26
8	Oleanolic acid		Orujo olive oil	Olive oil	27
9	Tarexerol acetate		Codieaum variegatum	Bark of Codieaum variegatum	28
10	Asiatic acid		Centella asiatica (L.) Urb	Whole plant of Centella asiatica (L.) Urb	29
11	Maniladiol		Chrysanthemum morifolium	Flowers of Chrysanthemum morifolium	30
12	Bartogenic acid		Barringtonia racemosa Roxb	Fruits of Barringtonia racemosa Roxb	31
13	Tormentic acid		Perilla frutescens (L.) Britt	Leaves of Perilla frutescens (L.) Britt	32
14	Glycyrrhetic acid		Glycyrrhiza glabra	Roots of Glycyrrhiza glabra	33
15	Corosolic acid		Lagerstroemia speciosa	Leaves of Lagerstroemia speciosa	34
16	23-Hydroxy butulinic acid		Pulsatilla chinensis	Roots of Pulsatilla chinensis	35
17	Euscaphic acid		Geum japonicum Thunb	Whole plant of Geum japonicum Thunb	36
18	Ursolic acid		Salvia officinalis & Ocimum sanctum Linn	Leaves of Salvia officinalis and Ocimum sanctum Linn	37
19	Ceanothic acid		Zizyphus jujuba Mill. var. spinosa (Bunge)	Roots of Zizyphus jujube	38
20	Lupenol		Cichorium spinosum	Aerial parts of Cichorium spinosum	39

---

2. Chemotherapy, chemoprevention and adjuvant to chemotherapy

The success of chemotherapy depends upon its administration at effective dose levels in an inflexible and programmed manner. However, such inflexible dosing schedules can rarely be followed in cancer therapy due to dose-limiting toxicities and related perversions in the recipient's quality of life. Thus, the cytotoxic efficacy of the chemotherapeutic agents cannot be exploited. There is a need of organ-protective adjuvants to continue the chemotherapy at effective dose levels along with either protecting normal body cells against chemotherapy-induced toxicities or sensitizing cancer cells to the cytotoxic effects of chemotherapy.^39,41 In addition to the protection of normal cells from cytotoxicity, an approach of sensitizing cancer cells to chemotherapy can help in reducing the dose of chemotherapeutic agents. The successful outcome of cancer chemotherapy depends on additional treatment with other agents given concurrently or after the primary treatment that lowers the untoward multi-organ damage inflicted by the chemotherapeutic agents. Obviously, such additional treatment is expected to boost the anticancer activity of the chemotherapeutic agents or at least should not antagonize their actions. The ideal outcomes of adjuvant therapy include protection of noncancerous cells leading to the maintenance of normal functioning of vital organs. Although the use of targeted drugs is an emerging trend in cancer therapy, it is not devoid of the associated toxicities, and hence, the use of cytotoxic drugs for cancer treatment is universally recommended.⁴² Obviously, the co-administration of organ-protective adjuvant therapy is warranted, and there is a need of adjuvants, which can synergistically contribute to the effects of chemotherapy.

3. Multifunctionality of pentacyclic triterpenoids as adjuvants to chemotherapy

Pentacyclic triterpenoids are widely distributed in the plant kingdom, and their semisynthetic derivatives and synthetic analogs possess molecular globularity, which enables them to interact with multiple biological targets. Pentacyclic triterpenes contain 30-carbon skeleton having six-membered rings (ursanes and lanostanes) and five-membered rings (lupanes and hopanes). Pentacylic triterpenoids are secondary metabolites widespread in fruit peels, leaves and stem bark especially in Mediterranean plant species with a percentage availability of 0.1–3%.^43,44 Triterpenoids possess an organotropic nature and accumulate in multiple vital organs. The organ-protective efficacy of pentacyclic triterpenoids has been substantiated through preclinical evaluations. The protective efficacy of pentacyclic triterpenoids through organotrophism and interactions with different molecular targets is summarized in Fig. 1 and Table 2.

Fig. 1 Molecular targets with which pentacyclic triterpenoids prove its multifunctional adjuvants effect. The molecular targets on which pentacyclic triterpenoids like BET, betulinic acid; BOS, boswellic acid; ARJ, arjunolic acid; MAS, maslinic acid; MAD. madecassic acid; CEL, celastrol; PRI, pristimerin; OLE, oleanolic acid; TAR, tarexerol acetate; ASI, asiatic acid; MAN, maniladione; BAR, bartogenic acid; TOR, tormentic acid; GLY, glycyrrhetic acid; COR, corosolic acid; HBA, 23-hHydroxy betulinic acid; EUS, escaphic acid; URS, ursolic acid; CEN, cenothic acid; LUP, lupeol are acting, with which they will exert cytoprotective adjuvant effect to cancer chemotherapy.

Table 2 Pentacyclic triterpenoids acting as organotropic effect on vital organs and its responsible molecular mechanisms

S. no	Name of compound	Organ protective effect			Molecular mechanisms	References
		Heart	Kidney	Liver
1	Betulinic acid	✓	✓	✓	NFκ-B, p65, p50, Bax, Bcl-2, Bcl-xL, IL-1, COX-2, MMP-9, TNF-α, GSH, MPO, ICAM-1, VCAM-1, and VEGE	17 and 45–49
2	Boswellic acid	✓	✓	✓	NFκ-B, TNF-α, IL-1, Bcl-2, caspase-3, iNOS	50–52
3	Arjunolic acid	✓	✓	✓	GST, SOD, TNF-α, IL-2, GSH, JNK, Bcl2	53–56
4	Maslinic acid	✓	✓	✓	iGP, NrF2, Cox-2, Ap-1, NFκ-B	57–61
5	Madecassic acid	✓	✓	✓	iNOS, COX-2, TNF-α, IL-1, IL-6, NFκ-B, p65, ERK, p38	62–65
6	Celastrol	✓	✓	✓	NFκ-B, AP1, AP2, Bcl-2, Bcl-xL, COX-2, survivin, cyclin D1, MMP9, VEGF, iNOS, Hsp90, VEGFR, NrF2	24 and 66–70
7	Pristimerin	✓	NA	✓	NFκ-B, PARP-1, JNK, Bax, p27, Bcl-2, Bcl-xL, caspase-3, -8, -9, HSP-60	71–74
8	Oleanolic acid	✓	✓	✓	NFκ-B, m'TOR, caspases-3, -8, and -9, ICAM-1, VEGF, PARP-1, Akt, cyclin-D, p65, NrF2, TNF-α	16 and 75–79
9	Tarexerol acetate	✓	✓	✓	MMP-1, TNF-α, iNOS, COX-2, NFκ-B, IL-1, IL-6	80–82
10	Asiatic acid	✓	✓	✓	NFκ-B, iNOS, MAPK, caspases-2, -3, -8 and -9, PARP-1, Bcl-2, iGP, JNK, p38, MMP-9, PGE2, TNF-α, IL-1, IL-6	30 and 83–89
11	Maniladiol	NA	NA	NA	—	—
12	Bartogenic acid	NA	NA	NA	PGs and IL-1	31 and 90
13	Tormentic acid	✓	✓	✓	α and β DNA polymerase, GSH, NrF2, COX-2, TNF- α, iNOS	91–95
14	Glycyrrhetic acid	✓	✓	✓	Cytochrome C, Bcl-2, Bcl- xL, Bak, caspase-3, Caspase-8, PPARγ	96–100
15	Corosolic acid	✓	✓	✓	NFκ-B, MAPK, IAP-1, caspase-8, -9 and -3, Bcl-2, iEBV-EA	101–104
16	23-Hydroxy butulinic acid	NA	NA	NA	Pgp and MDR	105 and 106
17	Euscaphic acid	✓	NA	NA	iα DNA polymerase	91 and 107
18	Ursolic acid	✓	✓	✓	NFκ-B, p38, MAPK, Bcl-2, Bax, ICAM-1, p53, p21, PKC, Cyclin D1, -D2, EGFR, ERK, TNF-α	108–111
19	Ceanothic acid	NA	NA	NA	—	—
20	Lupenol	✓	✓	✓	NFκ-B, survivin, Bax, caspase-3, -8, -9, p53, cyclin-D, Akt	112–114

---

Triterpenoids are neither conservative cytotoxic agents nor monotargeted drugs that inimitably target the single pathway. Some synthetic triterpenoids possess multipronged effects on cancer, inflammation, oxidative stress, proliferation of cancer cells, apoptosis and cytoprotection.¹¹⁵

3.1. Molecular pathways underlying protective effects of pentacyclic triterpenoids

3.1.1. Upregulation of NrF2 pathway for cytoprotection. NrF2 is also called a cap‘n’collar bZIP transcription factor. It controls the expression of several enzymes that protect against oxidative stress.¹¹⁶ NrF2 consists of six highly conservative domains, Neh1 to Neh6; Neh2 is an N-terminal domain that takes part in redox-dependent regulation of protein stability due to its attachment to Kelch-like ECH-associated binding protein (Keap-1) and conjugation with ubiquitin.¹¹⁷ Once NrF2 protein enters and stabilizes inside the nucleus, it gets dimerized with Maf proteins and transactivates several antioxidant enzymes.¹¹⁸ NrF2 is a cell-signaling transcriptional factor that generates cytoprotective phase II antioxidant enzymes such as GST, SOD, CAT, NQO1 and HO-1.^119,120 These enzymes are responsible for detoxifying harmful materials in the body. Phase II antioxidant enzymes are responsible for the organotropic and chemoprotective effect from anticancer drugs like cisplatin.¹²⁰

A study by Yap et al. concludes that maslinic acid and oleanolic acid increase the NrF2 expression and nuclear translocation up to 172% and 124%, respectively. This finding was validated through estimations of phase-II antioxidant like HO-1 and NQO1 in HepG2 cell lines. Thus, the organ-protective efficacy of maslinic acid and oleanolic acid is credited to their effects on the NrF2 pathway.⁶⁰ Another triterpenoid, celastrol, increases the expression of HO-1 via NrF2 translocation in the HaCat cell lines. Through NrF2 driven HO-1 expression, celastrol exerts anti-inflammatory effect and also reverts TNF-α and interferon-γ-induced ICAM expression in karatinocytes.⁷⁰ A study by Reisman et al. establishes that oleanolic acid, at a dose of 90 mg per kg per day administered to mice for three days, increases NrF2 translocation driven expression of HO-1 and NQO1 phase-II enzymes in the acetaminophen-induced hepatotoxicity model.⁷⁷ Liby et al. denote that the synthetic derivatives of oleanolic acid like CDDO and CDDO-imidazolide are strong inducers of NrF2 pathway and should be investigated for chemopreventive or chemotherapeutic agent. In their study, they used NrF2⁺⁺ and NrF2⁻˙⁻ mice as well as U937 and THP-1 cell lines. The northern blot analysis of vital organs and estimations of HO-1 induction substantiate that triterpenoids may also inhibit AKT and PKC pathway.¹²¹ A synthetic derivative of oleanolic acid, CDDO-methyl amide, induces the translocation of NrF2. Therefore, NrF2 knockout mice were used to verify the translocation factor via immunohistochemisty and sterologic analysis in the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridin (MPTP)-induced parkinsonism in fibroblast cells, which shows the increased levels of GSH, HO-1 and NQO1 and revert the neurotoxicity.¹²² Recently, patents have been filed for synthetic derivative of triterpenoids for their NrF2 translocation driven organ-protective effects in various diseases associated with increased oxidative stress.¹²³

An interaction of pentacyclic triterpenoids with Keap-1 leads to the accumulation of NrF2 in the cell nucleus and induces an antioxidant response element (ARE)-driven gene expression, which is the most important regulator of cell defense against chemical/oxidative stress.^41,124 Chemotherapeutic agents like doxorubicin affect the functioning of vital organs through oxidative stress. Hence, it can be postulated that pentacyclic triterpenoids are agents, which induce nuclear translocation of NrF2 (ref. 92, 121–123 and 125) and protect the vital organs without inhibiting the cytotoxic efficacy of chemotherapeutic agent in cancer cells.

3.1.2. NFκ-B inhibition for cytoprotection. The activation of NFκ-B pathway is a common process in the pathogenesis of multiple malignancies including leukemias, lymphomas, and solid tumors of breast, ovary, prostate, and colon.¹²⁶ A downregulation of the NFκ-B pathway by natural product can be a rational mode to curb cancer growth.¹²⁷ NFκ-B is implicated in cytoprotection from undergoing apoptosis in response to DNA damage exercise by chemotherapy. The NFκ-B pathway is regulated by diverse signal transduction cascades that include the activities of IKβ kinases, IKKα and IKKβ. The degradation of IKβ causes the translocation of NFκ-B from the cytoplasm to nucleus, which further activates cellular gene expression. The downregulation of the NFκ-B pathway increases the sensitivity of cells to apoptosis.^128,129 Agents inhibiting the NFκ-B pathway decrease the expression of VCAM-1 and ICAM-1 in endothelial cells.^61,129,130 Thus, an approach of inhibiting the NFκ-B pathway through a concurrent administration of pentacyclic triterpenoids may increase the efficacy of cancer chemotherapy with reduced cytotoxicity.¹³¹

Semisynthetic acyl derivatives of Boswellic acid are reported to inhibit NFκ-B pathway in the different cancer cell lines. The systematic evaluation of such compounds may prove a new era of anticancer agents.¹³² Arjunolic acid was also proven for its NFκ-B pathway modulation in the streptozotocin (STZ)-induced type 1 diabetes. The study also stated that pentacyclic triterpenoids have free radical scavenging potential and modulate MAPK and NFκ-B pathways. Arjunolic acid reverts cellular hepatotoxicity in diabetes.⁵⁶ Maslinic acid, a naturally occurring pentacyclic triterpenoid, modulates NFκ-B translocation in the Raji cell line and also inhibits COX-2 expression in them. The ability of maslinic acid to modulate NFκ-B and COX-2 indicates the probable antitumor and anti-inflammatory efficacy of maslinic acid.⁵⁸ Similarly, asiatic acid inhibits the nuclear translocation of NFκ-B through the possible degradation of IKKβ in lipopolysaccharide (LPS)-stimulated RAW cell line. This report emphasizes that asiatic acid also modulates the activities of p38, COX-2 and TOLL receptor, making it an ideal agent in the treatment of inflammation and cancer.⁸⁸ Another pentacyclic triterpenoid, madecassic acid, inhibits NFκ-B pathway and exerts inhibitory effect on iNOS, COX-2, IL-1, -6 and TNF-α expression in LPS-stimulated RAW cells. Inhibitory concentration ranges between 50 to 150 μM mL⁻¹, indicating potential anti-inflammatory and anticancer activity of the madecassic acid.⁶⁵ Another study shows that pretreatment with madecassoside reverts LPS-induced cytotoxicity in neonatal rat cardiomyocytes.⁶³ Another abundantly available triterpenoid, ursolic acid, inhibits NFκ-B translocation and suppresses COX-2, MMP-9 and TNF.¹⁰⁷ Similar effects are reported for lupeol, and it has been claimed as a potential agent in the treatment of skin carcinogenesis.¹³³

NFκ-B activation is involved in the progression of a tumor as well as in vital organ damage by chemotherapeutic agents. There is a homeostatic balance between NFκ-B and NrF2 expression in cellular microenvironment. The inhibition of NFκ-B increases the NrF2 translocation and provides cytoprotection against oxidative stress.¹³⁴ Pentacyclic triterpenoids are well reported for inhibiting the NFκ-B pathway^48,135 and hence can be projected to be a component of the arsenal against cancer as an anticancer as well as an organ-protective agent.

3.1.3. Free radical scavenging activity. Toxic electrophiles generated from chemotherapeutic agents and their metabolites exert oxidative stress.¹³⁶ Apart from this, the effects of chemotherapy generate free radicals like hydroxyl ion (OH˙), nitric oxide (NO˙), nitrites (NO₂˙), peroxyl radicals (RO₂˙), alkoxy radicals (RO˙), carbonate radicals (CO₃˙⁻) and superoxide anion (O₂˙⁻).¹³⁷ For example, the metabolites of doxorubicin, namely, semiquinone and quinone radicals, are more reactive than doxorubicin itself and hence exert severe cytotoxicity.¹³⁸ They impede the nucleophilic macromolecules of DNA, RNA, proteins and amino acids; these reactions in turn result in lipid peroxidation, DNA damage, cytoskeletal damage, protein oxidation and multiorgan toxicity.^139–141 Pentacyclic triterpenoids provide protection against oxidative stress through multiple modes like scavenging of free radicals, donating hydrogen ions to free radicals, depleting oxygen and directly binding and inactivating non-toxic radicals. Such effects of pentacyclic triterpenoids inhibit DNA damage and support the process of DNA repair.⁷

Betulinic acid reduces oxidative stress and augments antioxidant enzyme level like SOD, LDH, GST, and it also decreases lipid peroxidation in 7,12-dimethylbenzanthracene-induced carcinogenesis in mice.¹⁴² It has the potential to revert oxidative and nitrosative stress.⁴⁹ Other widely studied and easily extractable naturally occurring pentacyclic triterpenoids like oleanolic acid and its derivatives are reported to exert cytoprotective actions against hydrochloric acid and ethanol-induced gastric lesions in mice. They also exert cytoprotection against sodium taurocholate-induced cell damage in AGS cells. This study substantiates that the effect of oleanolic acid is better than that of sucralfate. These protective effects are associated with increased prostaglandins, SOD and GSH levels.¹⁴³ Another triterpenoid, asiatic acid, is reported to restore the levels of innate antioxidants in STZ-diabetic rats through the modulation of GST, SOD, and glutathione peroxidase (GPx) and thereby inhibit lipid peroxidation.¹⁴⁴ Similarly, derivatives of glycyrrhetic acid exert hepatoprotection,⁸⁵ corosolic acid reverts oxidative stress,¹⁴⁵ arjunolic acid inhibits arsenic-induced organ damage,²⁰ CCl₄-induced hepatotoxicity and STZ-induced diabetes in preclinical evaluations through various animal models. These protective effects are mediated either through free radical scavenging effects of these drugs or through a restoration of the innate antioxidants.^74,146

Cancer chemotherapy-induced oxidative stress is the primary reason for organ damage. Concurrent administration of potent antioxidants like pentacyclic triterpenoids can minimize chemotherapy-induced oxidative stress. Pentacyclic triterpenoids and their derivatives possess antioxidant potential.^{60,74,103,121–123,125,147–149} In addition to such potent antioxidant effects, pentacyclic triterpenoids also possess cytoprotective effect and can sensitize cancer cells to cytotoxic actions of chemotherapy. This dual effect through interaction with multiple biomolecules provides unique advantage in using pentacyclic triterpenoids as adjuvants to cancer chemotherapy.^37,150–154

3.1.4. Protein kinase C pathway inhibition for cytoprotection. Protein kinase C (PKCs) including serine/threonine kinases, manipulate a wide range of cellular processes and are involved in VCAM-1 induction.¹⁵⁵ Based on structure and cofactor regulations, PKC is classified in three different groups: first is diacylglycerol and Ca²⁺-dependent conventional isoforms like α, βI, βII and γ; second is a diacylglycerol-dependent but Ca²⁺-independent novel PKC isoform like δ, ε, η, θ, and μ; third is diacylglycerol and Ca²⁺-independent atypical isoforms like ι, λ and ζ.¹⁵⁶ In addition to all isoforms of the PKC family, PKC δ is a component which is activated in a calcium-independent manner^157,158 and extensively articulated in diverse tissues and has been implicated in an overabundance of cellular processes together with proliferation and apoptosis.^159,160 PKC δ is required for the survival and proliferation of cancer cells and not for the normal cell; with this hypothesis, the suppression of PKC δ leads to cell injury and death in tumors. PKC δ suppressing agents will lead to normal tissue-specific protective agents in chemotherapy.¹⁶¹ Moreover, silencing PKC family sub members may also sensitize chemotherapy-resistant cancer cells through phosphorylation to p-gp receptor.¹⁶²

Pentacyclic triterpenoids like betulinic acid, plantanic acid, oleanolic acid, asiatic acid, glycyrrhetic acid, ursolic acid, uvaol, asiaticoside and their derivatives possess PKC modulatory activity, which is supposed to contribute to their anticancer activity.^163–165 Maslinic acid exerts anticancer potential in Epstein–Barr virus-induced cancer in Raji cells by inhibiting the PKC pathway.¹⁶⁶ A recent study proves that maslinic acid, oleanolic acid and ursolic acid directly inhibit the βI, ζ, and δ isoforms of PKC in phorbol 12-myristate 13-acetate-induced Raji cells in a dose-dependent manner.¹⁶⁷ Similar inhibitory activity is reported for lupeol, alpha amyrin and their derivatives against cyclic AMP- and Ca²⁺-dependent PKC in rat liver and brain cells, where they produce anti-inflammatory activity.¹⁶⁸ Arjunolic acid reverts oxidative stress, and hyperglycaemia exerts PKC activation in diabetic mice and its related complications.¹⁶⁹

In addition to its role in cancer cell growth, PKC δ is associated with the process of inflammation. The PKC-inhibiting ability of pentacyclic triterpenoids thus can offer an added advantage if used as an adjuvant to chemotherapy. PKC inhibition may sensitize cancer cells to cytotoxic agents and thereby minimize the dose of chemotherapeutic agent.

3.1.5. Longevity cytoprotective pathways. Turnover of oxidative radicals is tightly controlled by different molecular pathways. Such fine control of oxidative stress determines the process of aging, detoxification and cell death.¹⁷⁰ The molecular pathways controlling oxidative stress contribute to the longevity of organisms. Certain components of these pathways determine responses of normal cells to drugs, oxidative stress, chemicals and pathogens.¹⁷¹ Cancer itself minimizes survival time;¹⁷² moreover, chemotherapeutic agents treat cancer but simultaneously are responsible for aberrant toxic effects on the vital organ as well as the immunity.^{1,92,94,100,173} Oxidative stress and disease condition as well as impaired functionality of vital organs ultimately results in the shortening of life.¹⁷⁴ The cytoprotective mechanisms of pentacyclic triterpenoids include their interactions with the components of longevity pathways like mitochondrial and endoplasmic reticulum protein response, like heat shock proteins (HSP), ROS responses like SOD, xenobiotic detoxification response like GST, insulin/IGF-1 signaling, autophagy and transcriptional factor like NrF2.^175–178 The reports on betulinic acid-induced inhibition DMBA-induced carcinogesis,¹⁴² oleanolic acid related restoration of GST activity,¹²³ and other pentacyclic triterpenoids associated cell signal transduction through SOD^95,179 etc. show their ability to affect longevity pathways. Similarly, cytoprotection exerted by celastrol through heat shock proteins,^24,180 avicin-induced selective apoptosis and autophagy in tumor cells, and reversal of the resistance of the cancer cell to cytotoxic drugs¹⁸¹ indicate the modulation of longevity pathways by pentacyclic triterpenoids.

Though cell longevity is driven by diverse signaling cascades like HSP, SOD, GST, IGF-1, JNK and Nrf2, the pentacyclic triterpenoids possess an ability to modulate a majority of these signaling pathways. In addition to these, they also modulate JNK.^72,182 Such multifunctionality of pentacyclic triterpenoids may add to longevity in cancer patients. Certain studies in this regard have concluded in agreement with the claims on longevity induced by pentacyclic triterpenoids.^178,183

4. Conclusion

The naturally occurring pentacyclic triterpenoids and their derivatives may prove to be safe, economic and easily available agents, which exert selective toxicities towards cancer cells while protecting normal ones. The biomolecules involved in the survival, growth and resistance to chemotherapy appear to be accessible to the actions of these multifunctional agents. The molecular pathway related to NFκ-B, NrF2, innate antioxidants, protein kinases and longevity pathways are targetable by the pentacyclic triterpenoids. This unique globularity in the actions of pentacyclic triterpenoids along with their selective cytotoxicity towards cancer cells points towards their substantial role as adjuvants to cancer chemotherapy.^{67,105,106,184–187} Systematic investigations on adjuvant-like role of pentacyclic triterpenoids in cancer chemotherapy could deliver agents that can be used as routine additives to cancer therapy. In addition to monotargeted novel treatment approaches, the use of validated adjuvants like pentacyclic triterpenoids can provide a sustainable approach in minimizing the doses of chemotherapeutic agents without affecting their cytotoxicity against cancer cells. Pentacyclic triterpenoids and their derivatives hold great promise as adjuvants in cancer chemotherapy.

Conflict of interest

Authors are disclosing that there are no conflicts of interest.

List of abbreviations

NrF2	Nuclear factor erythroid-derived 2-like 2
NFκ-B	Nuclear factor kappa B
PKC	Protein kinase C
Keap-1	Kelch-like ECH-associated binding protein
GST	Glutathion-S-transferase
SOD	Superoxide dismutase
CAT	Catalase
NQO1	NAD(P)H dehydrogenase (quinone 1)
HO-1	Heme oxygenase 1
TNF-α	Tumor necrosis factor-α
ICAM	Intercellular adhesion molecule 1
MPTP	1-Methyl-4-phenyl-1,2,3,4-tetrahydropyridin
ARE	Antioxidant response element
VCAM-1	Vascular cell adhesion protein 1
STZ	Streptozotocin
MAPK	Mitogen-activated protein kinases
COX-2	Cyclooxygenase-2
iNOS	Inducible nitric oxide synthase
LPS	Lipopolysaccharide
IL	Interleukin
MMP-9	Matrix metallopeptidase 9
GSH	Glutathione
GPx	Glutathione peroxidase
HSP	Heat shock proteins
ROS	Reactive oxygen species
IGF-1	Insulin growth factor-1
JNK	c-Jun N-terminal kinase

Acknowledgements

The first author is thankful to the department of science and technology (DST), India, for receiving the research fellowship with order no. SR/WOS-A/LS-121/2011 (G) for present work.

References

1. M. Mohan, S. Kamble, P. Ghadi and S. Kasture, Food Chem. Toxicol., 2010, 48, 436–440.
2. X. Zhang, M. Su, Y. Chen, J. Li and W. Lu, Molecules, 2013, 18, 6491–6503.
3. M. Singh, P. Chaudhry, F. Fabi and E. Asselin, BMC Cancer, 2013, 13, 1–9.
4. D. M. K. Keefe and E. H. Bateman, Nat. Rev. Clin. Oncol., 2012, 9, 98–109.
5. R. Sarin, J. Cancer Res. Ther., 2008, 4, 1–3.
6. C. Pisano, S. C. Cecere, M. D. Napoli, C. Cavaliere, R. Tambaro, G. Facchini, C. Scaffa, S. Losito, A. Pizzolorusso and S. Pignata, J. Drug Delivery, 2013, 2013, 1–12.
7. C. R. Culy and C. M. Spencer, Drugs, 2001, 61, 641–684.
8. N. Tas, B. Bakar, M. O. Kasimcan, S. Gazyagci, S. Ayva, K. Kılınc and C. Evliyaoglu, Int. J. Care Injured, 2010, 41, 1068–1074.
9. W. Caceres, L. Baez, I. Aponte, N. Rodriguez and A. Maldonado, Bol. - Asoc. Med. P. R., 1997, 89, 184–188.
10. J. Auta, E. Costa, J. Davis and A. Guidotti, Neuropharmacology, 2004, 46, 397–403.
11. Y. S. Shin, S. J. Song, S. Kang, H. S. Hwang, Y. S. Jung and C. H. Kim, J. Appl. Toxicol., 2014, 34, 191–204.
12. K. El-Bayoumy, Mutat. Res., 2001, 475, 123–139.
13. I. Cordero-Herrera, S. Cuello, L. Goya, Y. Madrid, L. Bravo, C. Camara and S. Ramos, Food Chem. Toxicol., 2013, 59, 554–563.
14. B. Das and K. Chaudhuri, RSC Adv., 2014, 4, 20964–20973.
15. P. Paul, M. K. Unnikrishnan and A. N. Nagappa, Indian J. Nat. Prod. Resour., 2011, 2, 137–150.
16. T. K. Yim, W. K. Wu, W. F. Pak and K. M. Ko, Phytother. Res., 2001, 15, 589–592.
17. E. Eksioglu-Demiralp, E. R. Kardas, S. Ozgul, T. Yagc, H. Bilgin, O. Sehirli, F. Ercan and G. Sener, Phytother. Res., 2010, 24, 325–332.
18. L. M. Schuchter, Oncology, 1997, 11, 505–512.
19. C. Chandramu, R. D. Manohar, D. G. L. Krupadanam and R. V. Dashavantha, Phytother. Res., 2003, 17, 129–134.
20. B. Mahajan, S. C. Taneja, V. K. Sethi and K. L. Dhar, Phytochemistry, 1995, 39, 453–455.
21. P. Manna, M. Sinha, P. Pal and P. C. Sil, Chem.-Biol. Interact., 2007, 170, 187–200.
22. A. R. Martín, R. D. Vázquez, A. Fernández-arche and V. Ruiz-gutiérrez, Free Radical Res., 2006, 40, 295–302.
23. O. A. Oyedeji and A. J. Afolayan, Pharm. Biol., 2005, 43, 249–252.
24. J. Lee, T. H. Koo, H. Yoon, H. S. Jung, H. Z. Jin, K. Lee, X. Y. Hong and J. J. Lee, Biochem. Pharmacol., 2006, 72, 1311–1321.
25. A. Salminen, M. Lehtonen, T. Paimela and K. Kaarniranta, Biochem. Biophys. Res. Commun., 2010, 394, 439–442.
26. D. Q. Luo, et al., Pest Manage. Sci., 2005, 61, 85.
27. R. Rodrıguez-Rodrıguez, M. D. Herrera, J. S. Perona and V. RuizGutierrez, Br. J. Nutr., 2004, 92, 635–642.
28. S. Chauhan and A. Singh, Rev. Inst. Med. Trop. Sao Paulo, 2011, 53, 265–270.
29. M. Bonfill, S. Mangas, R. M. Cusido, L. Osuna, M. T. Pinol and J. Palazon, Biomed. Chromatogr., 2005, 20, 151–153.
30. M. Ukiya, T. Akihisa, H. Tokuda, H. Suzuki, T. Mukainaka, E. Ichiishi, Y. Kasahara and H. Nishino, Cancer Lett., 2002, 177, 7–12.
31. K. R. Patil, C. R. Patil, R. B. Jadhav, V. K. Mahajan, P. R. Patil and P. S. Gaikwad, J. Evidence-Based Complementary Altern. Med., 2011, 2011, 1–7.
32. J. H. Chen, Z. H. Xia and R. X. Tan, J. Pharm. Biomed. Anal., 2003, 32, 1175–1179.
33. C. Sabbioni, R. Mandrioli, A. Ferranti, F. Bugamelli, M. A. Saracino, G. C. Forti, S. Fanali and M. A. Raggi, J. Chromatogr. A, 2005, 1081, 65–71.
34. N. Bai, K. He, M. Roller, B. Zheng, Z. Chen, Z. Hao, T. Peng and A. Zheng, J. Agric. Food Chem., 2008, 56, 11668–11674.
35. W. Ye, N. Ji, S. Zhao, J. Lio and T. Ye, Phytochemistry, 1996, 42, 799–802.
36. H. Xu, F. Zeng, M. Wan and K. Sim, J. Nat. Prod., 1996, 59, 7643–7645.
37. A. Shukla, K. Kaur and P. Ahuja, Online Int. Interdiscipl. Res. J., 2013, 3, 9–14.
38. S. Lee, B. Tin and K. C. Liu, Phytochemistry, 1996, 43, 847–851.
39. E. Melliou, P. Magiatis and L. Skaltsounis, J. Agric. Food Chem., 2003, 51, 1289–1292.
40. B. B. Aggarwal and S. Shishodia, Biochem. Pharmacol., 2006, 71, 1397–1421.
41. I. M. Copple, C. E. Goldring, N. R. Kitteringham and B. K. Park, Toxicology, 2008, 246, 24–33.
42. Y. Li, S. W. A. Himaya and S. Kim, Molecules, 2013, 18, 7886–7909.
43. S. Jager, H. Trojan, T. Kopp, M. N. Laszczyk and A. Scheffler, Molecules, 2009, 14, 2016–2031.
44. P. K. Chaturvedi, K. Bhui and Y. Shukla, Cancer Lett., 2008, 263, 1–13.
45. Y. Takada and B. B. Aggarwal, J. Immunol., 2003, 171, 3278–3286.
46. H. Kasperczyk, K. L. Ferla-Bruhl, M. A. Westhoff, L. Behrend, R. Zwacka, K. Debatin and S. Fulda, Oncogene, 2005, 24, 6945–6956.
47. F. B. Mullauer, J. H. Kessler and J. P. Medema, Apoptosis, 2009, 14, 191–202.
48. J. J. Yoon, Y. J. Lee, J. S. Kim, D. G. Kang and H. S. Lee, Biochem. Biophys. Res. Commun., 2010, 391, 96–101.
49. Q. Lu, N. Xia, H. Xu, L. Guo, P. Wenzel, A. Daiber, T. Munzel, U. Forstermann and H. Li, Nitric Oxide, 2011, 24, 132–138.
50. T. Akihisa, K. Tabata, N. Banno, H. Tokuda, R. Nishihara, Y. Nakamura, Y. K. Imura, K. Y. Asukawa and T. Suzuki, Biol. Pharm. Bull., 2006, 29, 1976–1979.
51. S. Roy, S. Khanna, A. V. Krishnaraju, G. V. Subbaraju, T. Yasmin, D. Bagchi and C. K. Sen, Antioxid. Redox Signaling, 2006, 8, 653–660.
52. Y. Takada, H. Ichikawa, V. Badmaev and B. B. Aggarwal, J. Immunol., 2006, 176, 3127–3140.
53. P. Manna, M. Sinha and P. C. Sil, Arch. Toxicol., 2008, 82, 137–149.
54. J. Ghosh, J. Das, P. Manna and P. C. Sil, Toxicol. in Vitro, 2008, 22, 1918–1926.
55. J. Ghosh, J. Das, P. Manna and P. C. Sil, Toxicology, 2010, 268, 8–18.
56. P. Manna, J. Das, J. Ghosh and P. C. Sil, Free Radical Biol. Med., 2010, 48, 1465–1484.
57. X. Wen, P. Zhang, J. Liu, L. Zhang, X. Wu, P. Ni and H. Sun, Bioorg. Med. Chem. Lett., 2006, 16, 722–726.
58. Y. W. Hsum, W. T. Yew, P. L. V. Hong, K. Soo, L. S. Hoon, Y. C. Chieng and L. Y. Mooi, Planta Med., 2011, 77, 152–157.
59. A. H. Shaikh, S. N. Rasool, M. A. Kareem, G. S. Krushna, P. M. Akhtar and K. L. Devi, J. Med. Food, 2012, 15, 741–746.
60. W. H. Yap, S. K. Khoo, H. S. K. Ho and Y. M. Lim, Biomedicine & Preventive Nutrition, 2012, 2, 51–58.
61. M. J. Yin, Y. Yamamoto and R. B. Gaynor, Nature, 1998, 396, 77–80.
62. M. K. Shanmugam, A. H. Nguyen, A. P. Kumar, B. H. K. Tan and G. Sethi, Cancer Lett., 2012, 320, 158–170.
63. W. Cao, X. Li, X. Zhang, Y. Hou, A. Zeng, Y. Xie and S. Wang, Int. Immunopharmacol., 2010, 10, 723–729.
64. K. Vohra, G. Pal, S. Gupta, S. Singh and Y. Bansal, Pharmacologyonline, 2011, 2, 440–462.
65. J. Won, J. Shin, H. Park, H. Jung, D. Koh, B. Jo, J. Lee, K. Yun and K. Lee, Planta Med., 2010, 76, 251–257.
66. S. P. Preetha, M. Kanniappan, E. Selvakumar, M. Nagaraj and P. Varalakshmi, Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol., 2006, 143, 333–339.
67. D. He, Q. Xu, M. Yan, P. Zhang, X. Zhou, Z. Zhang, W. Duan, L. Zhong, D. Ye and W. Chen, BMC Cancer, 2009, 9, 1–9.
68. S. Y. Jang, S. Jang and J. Ko, Cancer Lett., 2011, 300, 57–65.
69. M. S. Willis and C. Patterson, Circulation, 2010, 122, 1740–1751.
70. W. Y. Seo, A. R. Goh, S. Ju, H. Y. Song, D. Kwon, J. Jun, B. C. Kim, S. Y. Choi and J. Park, Biochem. Biophys. Res. Commun., 2011, 407, 535–540.
71. C. Wu, M. Chan and W. Chen, Mol. Cancer Ther., 2005, 4, 1277–1285.
72. J. Byun, M. Kim, D. Eum, C. Yoon, W. Seo, K. H. Park, W. Hyun, Y. Lee, J. Lee, M. Yoon and S. Lee, Mol. Pharmacol., 2009, 76, 734–744.
73. J. C. R. Vellosa, N. M. Khalil, V. O. Gutierres, V. Santos, M. Furlan, I. L. Brunetti and O. M. Oliveira, Braz. J. Pharm. Sci., 2009, 45, 99–107.
74. H. Sassa, K. Kogure, Y. Takaishi and H. Terada, Free Radical Biol. Med., 1994, 17, 201–207.
75. R. D. Couch, R. G. Browning, T. Honda, W. G. Gribble, D. L. Wright, M. B. Sporn and A. C. Anderson, Bioorg. Med. Chem. Lett., 2005, 15, 2215–2219.
76. N. B. Janakiram, C. Indranie, S. V. Malisetty, P. Jagan, V. E. Steele and C. V. Rao, Pharm. Res., 2008, 25, 2151–2157.
77. (a) D. Deeb, X. Gao, H. Jiang, S. A. Dulchavsky and S. C. Gautam, Prostate, 2009, 69, 851–860; (b) S. A. Reisman, L. M. Aleksunes and C. D. Klaassen, Biochem. Pharmacol., 2009, 77, 1273–1282.
78. C. R. Patil, R. B. Jadhav, P. K. Singh, S. Mundada and P. R. Patil, Phytother. Res., 2010, 24, 33–37.
79. M. Shyu, T. Kao and G. Yen, J. Agric. Food Chem., 2010, 58, 6110–6118.
80. A. Jutiviboonsuk, H. Zhang, T. P. Kondratyuk, A. Herunsalee, W. Chaukul, J. M. Pezzuto, H. S. Fong and N. Bunyapraphatsara, Pharm. Biol., 2007, 45, 185–194.
81. A. Kamboj and A. K. Saluja, Pharmacogn. Rev., 2009, 3, 364–374.
82. X. Yao, G. Li, Q. Bai, H. Xu and C. Lu, Int. Immunopharmacol., 2013, 15, 316–324.
83. A. Gnanapragasam, K. K. Ebenezar, V. Sathish, P. Govindaraju and T. Devaki, Life Sci., 2004, 76, 585–597.
84. Y. Hsu, P. Kuo, L. Lin and C. Lin, J. Pharmacol. Exp. Ther., 2005, 313, 333–344.
85. H. G. Jeong, H. J. You, S. J. Park, A. Moon, Y. C. Chung, S. K. Kang and H. Chun, Pharmacol. Res., 2002, 46, 221–227.
86. L. Zhang, J. Chen, Y. Gong, J. Liu, L. Zhang, W. Hu and H. Sun, Chem. Biodiversity, 2009, 6, 864–874.
87. K. Y. Lee, O. Bae, S. Serfozo, S. Hejabian, A. Moussa, M. Reeves, W. Rumbeiha, S. D. Fitzgerald, G. Stein, S. Baek, J. Goudreau, M. Kassab and A. Majid, Stroke, 2012, 43, 1632–1638.
88. K. Yun, J. Kim, K. Lee, S. Jeong, H. Park, H. Jung, Y. Cho, K. Yun and K. Lee, Int. Immunopharmacol., 2008, 8, 431–441.
89. E. Y. Vouffo, F. M. Donfack, R. J. Temdie, F. T. Ngueguim, J. H. Donfack, D. D. Dzeufiet, A. B. Dongmo and T. Dimo, J. Exp. Integr. Med., 2012, 2, 337–344.
90. T. J. Thomas, B. Panikkar, A. Subramoniam, M. K. Nair and K. R. Panikkar, J. Ethnopharmacol., 2002, 82, 223–227.
91. C. Murakami, K. Ishijima, M. Hirota, K. Sakaguchi, H. Yoshida and Y. Mizushina, Biochim. Biophys. Acta, 2002, 1596, 193–200.
92. Y. Kim, J. Choi, H. Rim, H. Kang, S. Chang, J. Park, H. Park, J. W. Choi, S. Kim and K. Lee, Biol. Pharm. Bull., 2011, 34, 906–911.
93. H. Sheng and H. Sun, Nat. Prod. Rep., 2011, 28, 543–593.
94. S. Sohn, H. Rim, Y. Kim, J. Choi, J. Park, H. Park, J. Choi, S. K. Kim, S. Jeong and K. Lee, Biol. Pharm. Bull., 2011, 34, 1508–1513.
95. C. Chang, S. Huang, S. Lin, S. Amagaya, H. Ho, W. Hou, P. Shie, J. Wu and G. Huang, Food Chem., 2011, 127, 1131–1137.
96. H. Nishino, K. Kitagawa and A. Iwashima, Cardnogenesis, 1984, 5, 1529–1530.
97. S. Saito, S. Nagase, M. Kawase and Y. Nagamura, Eur. J. Med. Chem., 1996, 31, 557–574.
98. E. Sohn, D. Kang and H. Lee, Pharmacol. Toxicol., 2003, 93, 116–122.
99. Y. Satomi, H. Nishino and S. Shibata, Anticancer Res., 2005, 25, 4043–4048.
100. C. S. Lee, Y. J. Kim, M. S. Lee, E. S. Han and S. J. Lee, Life Sci., 2008, 83, 481–489.
101. N. Banno, T. Akihisha, H. Tokuda, K. Yasukawa, K. Higashihara, M. Ukiya, K. Wantanabe, Y. Kimura, J. Hasegawa and H. Nishino, Biosci., Biotechnol., Biochem., 2004, 68, 85–90.
102. K. S. Shim, S. Lee, S. Y. Ryu, Y. K. Min and S. H. Kim, Phytother. Res., 2009, 23, 1754–1758.
103. M. Yin, M. Lin, M. Mong and C. Lin, J. Agric. Food Chem., 2012, 60, 7697–7701.
104. Y. Xu, R. Ge, J. Du, H. Xin, T. Yi, J. Sheng, Y. Wang and C. Ling, Cancer Lett., 2009, 284, 229–237.
105. Y. Zheng, F. Zhou, X. Wu, X. Wen, Y. Li, B. Yan, J. Zhang, G. Hao, W. Ye and G. Wang, J. Ethnopharmacol., 2010, 128, 615–622.
106. D. Zhang, C. Shu, J. Chen, K. Sodani, J. Wang, J. Bhatnagar, P. Lan, Z. Ruan and Z. Xiao, Mol. Pharmaceutics, 2012, 9, 3147–3154.
107. C. H. George, S. R. Barberini-Jammaers and C. T. Muller, Expert Opin. Ther. Pat., 2008, 18, 1–19.
108. S. Shishodia, S. Majumdar, S. Banerjee and B. B. Aggarwal, Cancer Res., 2003, 63, 4375–4383.
109. Y. Hsu, P. Kuo and C. Lin, Life Sci., 2004, 75, 2303–2316.
110. S. Senthil, G. Chandramohan and K. V. Pugalendi, Int. J. Cardiol., 2007, 119, 131–133.
111. K. Takada, T. Nakane, K. Masuda and H. Ishii, Phytomedicine, 2011, 17, 1114–1119.
112. L. Vidya and P. Varalakshmi, Fitoterapia, 2000, 71, 535–543.
113. R. Saleem, S. I. Ahmad, M. Ahmed, Z. Faizi, S. Zikr-ur-rehman, M. Ali and S. F. Aizi, Biol. Pharm. Bull., 2003, 26, 41–46.
114. N. Nigam, S. Prasad, J. George and Y. Shukla, Biochem. Biophys. Res. Commun., 2009, 381, 253–258.
115. K. T. Liby, M. M. Yore and M. B. Sporn, Nat. Rev., 2007, 7, 357–369.
116. H. Merikallio, P. Paakko, V. L. Kinnula, T. Harju and Y. Soini, Hum. Pathol., 2012, 43, 577–584.
117. V. O. Tkachev, E. B. Menshchikova and N. K. Zenkov, Biochemistry, 2011, 76, 407–422.
118. T. W. Kensler and N. Wakabayashi, Carcinogenesis, 2010, 31, 90–99.
119. J. D. Hayes, M. McMahon, S. Chowdhry and A. T. Dinkova-Kostova, Antioxid. Redox Signaling, 2010, 13, 1714–1748.
120. K. Jung and M. Kwak, Molecules, 2010, 15, 7266–7291.
121. K. Liby, T. Hock, M. M. Yore, N. Suh, A. E. Place, R. Risingsong, C. R. Williams, D. B. Royc, T. Honda, Y. Honda, G. W. Gribble, N. Hill-Kapturczak, A. Agarwal and M. B. Sporn, Cancer Res., 2005, 65, 4789–4798.
122. L. Yang, N. Y. Calingasan, B. Thomas, R. K. Chaturvedi and M. Kiaei, PLoS One, 2009, 4, 1–14.
123. M. B. Sporn, K. T. Liby, G. W. Gribble, T. Honda, R. M. Kral and C. J. Meyer, US Pat., 8129 429 B2, 2012.
124. J. D. Hayes, M. McMahon, S. Chowdhry and A. T. Dinkova-Kostova, Antioxid. Redox Signaling, 2010, 13, 1714–1748.
125. M. B. Sporn, K. T. Liby, M. M. Yore, L. Fu, J. M. Lopchuk and G. W. Gribble, J. Nat. Prod., 2011, 74, 537–545.
126. B. Rayet and C. Gelinas, Oncogene, 1999, 18, 6938–6947.
127. S. Prasad, J. Ravindran and B. B. Aggarwal, Mol. Cell. Biochem., 2010, 336, 25–37.
128. A. D. J. Van, S. J. Martin, T. Kafri, D. R. Green and I. M. Verma, Science, 1996, 274, 787–789.
129. C. Y. Wang, M. W. Mayo and A. S. J. Baldwin, Science, 1996, 274, 784–787.
130. Y. Yamamoto, M. J. Yin, K. M. Lin and R. B. Gaynor, J. Biol. Chem., 1999, 274, 27307–27314.
131. Y. Yamamoto and R. B. Gaynor, J. Clin. Invest., 2001, 107, 135–142.
132. A. Kumar, B. A. Shah, S. Singh, A. Hamid, S. K. Singh, V. K. Sethi, A. K. Saxena, J. Singh and S. C. Taneja, Bioorg. Med. Chem. Lett., 2012, 22, 431–435.
133. S. Prasad, E. Madan, N. Nigam, P. Roy, J. George and J. Shukla, Cancer Biol. Ther., 2009, 8, 1632–1639.
134. J. K. Kundu and Y. Surh, Pharm. Res., 2010, 27, 999.
135. V. R. Yadav, S. Prasad, B. Sung, R. Kannappan and B. B. Aggarwal, Toxins, 2010, 2, 2428–2466.
136. S. M. Attia, Oxid. Med. Cell. Longevity, 2010, 3, 238–253.
137. C. Houée-Levin and K. Bobrowski, J. Proteomics, 2013, 92, 51–62.
138. O. O. Shevchuk, E. A. Posokhova, L. A. Sakhno and V. G. Nikolaev, Exp. Oncol., 2012, 34, 314–322.
139. L. Bruton, K. Parker and I. Buxton, in Goodman and Gilman's annual of pharmacology and therapeutics, The mcGrow-Hill companies, USA, 11th edn, 2008, pp. 867–888.
140. H. Mohan, in The textbook of pathophysiology, Jaypee brother's medical publishers (P) ltd, India, 5th edn, 2005, pp. 38–41.
141. I. Bouhlel, K. Valenti, S. Kilani, I. Skandrani, M. B. Sghaier, A. Mariotte, M. Dijoux-Franca, K. Ghedira, I. Hininger-Favier and F. Laporte, Toxicol. in Vitro, 2008, 22, 1264–1272.
142. R. Kaur and S. Arora, Free Radicals Biol. Med., 2013, 65, 131–142.
143. M. Sánchez, C. Theoduloz, G. Schmeda-Hirschmann, I. Razmilic, T. Yáñez and J. A. Rodríguez, Life Sci., 2006, 79, 1349–1356.
144. V. Ramachandran and R. Saravanan, J. Funct. Foods, 2013, 5, 1077–1087.
145. Y. Yamaguchi, K. Yamada, N. Yoshikawa, K. Nakamura, J. Haginaka and M. Kunitomo, Life Sci., 2006, 79, 2474–2479.
146. P. Manna, J. Ghosh, J. Das and P. C. Sil, Toxicol. Appl. Pharmacol., 2010, 244, 114–129.
147. L. I. Somova, F. O. Shode, P. Ramnanan and A. Nadar, J. Ethnopharmacol., 2003, 84, 299–305.
148. H. S. Chung, Int. J. Food Sci. Nutr., 2009, 14, 49–53.
149. T. Morita, Am. J. Hypertens., 2010, 23, 821.
150. P. Bigoniya, A. Shukla and C. S. Singh, Int. J. Phytomed., 2010, 2, 240–254.
151. X. Peng, J. Liu, Z. Han, X. Yuan, H. Luo and M. Qiu, Food Chem., 2013, 141, 920–926.
152. T. B. Nguelefack, H. K. Mbakam, L. K. Tapondjou, P. Watcho, E. P. Nguelefack-Mbuyo, B. K. Ponou, A. Kamanyi and H. A. Park, Arch. Pharmacal Res., 2011, 34, 543–550.
153. C. Grace-Lynn, I. Darah, Y. Chen, L. Y. Latha, S. L. Jothy and S. Sasidharan, Molecules, 2012, 17, 11185–11198.
154. A. Manosroi, P. Jantrawut, E. Ogihara, A. Yamamoto, M. Fukatsu, K. Yasukawa, H. Tokuda, N. Suzuki, J. Manosroi and T. Akihisa, Chem. Biodiversity, 2013, 10, 1448–1463.
155. P. J. Parker and J. Murray-Rust, J. Cell Sci., 2004, 117, 131–132.
156. S. Yan, E. Harja, M. Andrassy, T. Fujita and A. M. Schmidt, J. Am. Coll. Cardiol., 2006, 48, A47–A55.
157. W. S. Liu and C. A. Heckman, Cell Signal, 1998, 10, 529–542.
158. U. Kikkawa, H. Matsuzaki and T. Yamamoto, J. Biochem., 2002, 132, 831–839.
159. T. A. De Vries-Seimon, A. M. Ohm, M. J. Humphries and M. E. Reyland, J. Biol. Chem., 2007, 282, 22307–22314.
160. M. J. Humphries, A. M. Ohm, J. Schaack, T. S. Adwan and M. E. Reyland, Oncogene, 2008, 27, 3045–3053.
161. N. Pable and Z. Dong, Oncotarget, 2012, 3, 107–111.
162. L. Zhao, H. Xu, J. Qu, W. Zhao, Y. Zhao and J. Wang, Asian Pac. J. Cancer Prev., 2012, 13, 3631–3636.
163. T. Fujioka, Y. Kashiwada, R. E. Kilkuskie, L. M. Cosentino, L. M. Ballas, J. B. Jiang, W. P. Janzen, I. S. Chen and K. H. Lee, J. Nat. Prod., 1994, 57, 243–247.
164. B. H. Wang and G. M. Polya, Phytochemistry, 1996, 41, 55–63.
165. L. Moon, Y. M. Ha, H. J. Jang, H. S. Kim, M. S. Jun, Y. M. Kim, Y. S. Lee, D. H. Lee, K. H. Son, H. J. Kim, H. G. Seo, J. H. Lee, Y. S. Kim and K. C. Chang, J. Ethnopharmacol., 2011, 133, 336–344.
166. L. Y. Mooi, N. A. Wahab, N. H. Lajis and A. M. Ali, Chem. Biodiversity, 2010, 7, 1267–1275.
167. L. Y. Mooi, W. T. Yew, Y. S. Hsum, K. K. Soo, L. S. Hoon and Y. C. Chieng, Asian Pac. J. Cancer Prev., 2012, 13, 1177–1182.
168. M. Hasmeda, G. Kweifio-Okai, T. Macrides and G. M. Polya, Planta Med., 1999, 65, 14–18.
169. P. Manna and P. C. Sil, Free Radical Res., 2012, 46, 815–830.
170. K. N. Lewis, J. Mele, J. D. Hayes and R. Buffenstein, Integr. Comp. Biol., 2010, 50, 829–843.
171. D. E. Shore and G. Ruvkun, Trends Cell Biol., 2013, 13, 409–420.
172. F. Fallah-Rostami, M. A. Tabari, B. Esfandiari, H. Aghajanzadeh and M. Y. Behzadi, N. Am. J. Med. Sci., 2013, 5, 207–212.
173. S. E. Jang, E. H. Joh, Y. T. Ahn, C. S. Huh, M. J. Han and D. H. Kim, Immunopharmacol. Immunotoxicol., 2013, 35, 396–402.
174. M. Maulik, D. Mc Fadden, H. Otani, M. Thirunavukkarasu and N. L. Parinandi, Oxid. Med. Cell. Longevity, 2013, 2013, 1–3.
175. D. E. Shore, C. E. Carr and G. Ruvkun, PLoS Genet., 2012, 8, 1–15.
176. M. T. Crow, Circ. Res., 2004, 95, 953–995.
177. F. Madeo, N. Tavernarakis and G. Kroemer, Nat. Cell Biol., 2010, 12, 842–846.
178. G. P. Sykiotis, J. G. Habeos, A. V. Samuelson and D. Bohmann, Current Opinion in Clinical Nutrition and Metabolic Care, 2011, 14, 41–48.
179. Y. Huang, J. Li, Q. Cao, S. Yu, L. Xiong-Wen, Y. Jin, L. Zhang, Y. Zou and J. Ge, Life Sci., 2006, 78, 2749–2757.
180. S. D. Westerheide, J. D. Bosman, B. N. A. Mbadugha, T. L. A. Kawahara, G. Matsumoto, S. Kim, W. Gu, J. P. Devlin, R. B. Silverman and R. I. Morimoto, J. Biol. Chem., 2004, 279, 56053–56060.
181. H. Wang, V. Haridas, J. U. Gutterman and Z. Xu, Commun. Integr. Biol., 2010, 3, 205–208.
182. T. Rabi and S. Banerjee, Mol. Carcinog., 2008, 47, 415–423.
183. C. Stack, D. Ho, E. Wille, N. Y. Calingasan, C. Williams, K. Liby, M. Sporn, M. Dumont and M. F. Beal, Free Radical Biol. Med., 2010, 49, 147–158.
184. M. L. Hyer, R. Croxton and M. Krajewska, Cancer Res., 2005, 65, 4799–4808.
185. V. H. Villar, M. Gomez, O. Vogler, J. M. Serra, J. Martin, V. Ruiz-Gutierrez, F. Barcelo and R. Alemany, Chem. Phys. Lipids, 2010, 163S, S57–S59.
186. K. Liby, T. Honda and C. R. Williams, Mol. Cancer Ther., 2007, 6, 2113–2119.
187. V. Zuco, R. Supino, S. C. Righetti, L. Cleris, E. Marchesi, C. Gambacorti-Passerini and A. Formelli, Cancer Lett., 2002, 175, 17–25.

---