Aglycone solanidine and solasodine derivatives: A natural approach towards cancer

Biomedicine & Pharmacotherapy 94 (2017) 446–457

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Review

Aglycone solanidine and solasodine derivatives: A natural approach towards cancer Abdul Hameeda , Shakeel Ijaza , Imran Shair Mohammadb,* , Kiran Sher Muhammadc , Naveed Akhtara , Haji Muhammad Shoaib Khana a b c

Department of Pharmacy, Faculty of Pharmacy and Alternative Medicines, The Islamia University of Bahawalpur, Bahawalpur, Punjab, 63100, Pakistan Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China Department of Zoology, University of Agriculture, Faisalabad, Pakistan

A R T I C L E I N F O

Article history: Received 5 June 2017 Received in revised form 26 July 2017 Accepted 27 July 2017 Keywords: Natural compounds Glycoalkaloids Chemotherapeutic Apoptosis

A B S T R A C T

Over the past few years, it was suggested that a rational approach to treat cancer in clinical settings requires a multipronged approach that augments improvement in systemic efficiency along with modification in cellular phenotype leads to more efficient cell death response. Recently, the combinatory delivery of traditional chemotherapeutic drugs with natural compounds proved to be astonishing to deal with a variety of cancers, especially that are resistant to chemotherapeutic drugs. The natural compounds not only synergize the effects of chemotherapeutics but also minimize drug associated systemic toxicity. In this review, our primary focus was on antitumor effects of natural compounds. Previously, the drugs from natural sources are highly precise and safer than drugs of synthetic origins. Many natural compounds exhibit anti-cancer potentials by inducing apoptosis in different tumor models, in-vitro and in-vivo. Furthermore, natural compounds are also found equally useful in chemotherapeutic drug resistant tumors. Moreover, these Phyto-compounds also possess numerous other pharmacological properties such as antifungal, antimicrobial, antiprotozoal, and hepatoprotection. Aglycone solasodine and solanidine derivatives are the utmost important steroidal glycoalkaloids that are present in various Solanum species, are discussed here. These natural compounds are highly cytotoxic against different tumor cell lines. As the molecular weight is concerned; these are smaller molecular weight chemotherapeutic agents that induce cell death response by initiating apoptosis through both extrinsic and intrinsic pathways. © 2017 Elsevier Masson SAS. All rights reserved.

Contents 1. 2. 3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steroidal alkaloids/Glycoalkaloids . . . . . . . . . . . . . . . . . Aglycone solanidine alkaloids . . . . . . . . . . . . . . . . . . . . 3.1. Solanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toxic effects of solanine . . . . . . . . . . . . 3.1.1. 3.1.2. Antitumor effects of solanine . . . . . . . Chaconine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. 3.2.1. Anticancer activity of chaconine . . . . . Antimetastasis of chaconine . . . . . . . . 3.2.2. Aglycone solasodine alkaloids . . . . . . . . . . . . . . . . . . . . Solamargine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Anticancer effect of solamargine . . . . . 4.1.1. Cytotoxicity in human hepatic cell line 4.1.2.

* Corresponding author. E-mail address: [email protected] (I.S. Mohammad). http://dx.doi.org/10.1016/j.biopha.2017.07.147 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

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5. 6. 7.

4.1.3. The activity of solamargine against breast cell carcinoma Solasonine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Solasodine rhamnose glycoside (SRGs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Authors contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Recently, Cancer is a principal cause of death [1], associated with the development of solid masses known as tumors. In clinics, the management of cancer includes chemotherapy, radiotherapy and surgical removal of tumor masses. In chemotherapy, lowmolecular-weight cytotoxic agents are used to be administered. Unfortunately, these cytotoxic agents kill not only the tumor cells but also the healthy cells which result in hair loss, bone marrow suppression, nausea and gastrointestinal tract lesion [2]. Previously, the majority of chemotherapeutic drugs showed cell death response through the induction of programmed cell death (Apoptosis) [3], however; apoptosis is not the only mean to kill and eradicate cancer cells [4,5]. Apoptosis can characterize by cell shrinkage, dilatation of endoplasmic reticulum, DNA fragmentation, chromatin condensation and the formation of apoptotic bodies [6,7] by extrinsic and intrinsic pathway or both. The extrinsic pathway (receptor mediated pathway) results in the activation of cell surface ligand death receptors such as TNFR, Fas and TRAIL receptors while the intrinsic (mitochondrial mediated pathway) pathway associated with the release of cytochrome-C into the cytoplasm, following the mitochondrial disruption and

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initiate caspase cascade by converting procaspase-9 to caspase-9 and caspase-9 further activate caspase-3 that cause irreversible cell death (apoptosis) [8] (Fig. 1). Previously, many Phytocompounds and their synthetic and semi-synthetic derivatives are the potential sources of cytotoxic agents [9]. Furthermore, clinical trials for new chemical entities (NCE) or drugs for assessment of their anticancer potentials; about 50% of these come from natural origin [10]. Solanum nigrum is a versatile member of Solanaceae family [11] and predominantly breeds in temperate climate region [12]. It is an annual branching herb having dull dark green leaves and small white flowers [13]. At maturation, the berries or fruits of this plant are small in size, black in color and globular in shape [14]. Traditionally, grinded leaves of young plant applied externally for the treatment of sores, carbuncles, swelling and injuries [15]. It has diuretic and antipyretic effect and exploits in the management of edema, inflammation [12] and mastitis [16]. It also used to treat stomach ache, jaundice, liver problems, toothache and many skin diseases [17]. In China and Japan, the entire plant was used in different types of cancer [18] such as liver [12], lungs, urinary bladder, larynx, and carcinoma of vocal cords [19]. Plant also illustrates a number of other pharmacological actions such as;

Fig. 1. Apoptosis; intrinsic i.e mitochondrial-mediated pathway and extrinsic or death receptor-mediated pathways [106].

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hepatoprotective [20–22], anti-ulcerogenic [23], anti-seizure [24], cytoprotective [25], antifungal [26], neuro-pharmacological [27], antioxidative [28,29], antimicrobial [30], larvicidal, molluscicide and acaricidal [31–33]. However, amongst a lot of reported pharmacological studies, the anticancer effects of this plant expand a high priority [34]. Anticancer phytochemicals present in Solanum nigrum include glycoproteins, polysaccharides, steroidal alkaloids and glycoalkaloids [12]. These glycoalkaloids include solanine, solamargine, solasonine and solasodine [35,36]. In this review, we studied different steroidal glycoalkaloids present in Solanum nigrum concerning their chemical structures and hydrolysis, the level of cytotoxicity, along with their mode of action. 2. Steroidal alkaloids/Glycoalkaloids Glycoalkaloids are present in more than 350 plant species. Each species has a pair of glycoalkaloids, which has a similar aglycone moiety but different carbohydrate side-chain [37]. Several Solanum species also synthesize steroidal alkaloids, and their glycoalkaloids are natural toxins which demonstrate antitumor, teratogenic, antifungal, antiviral and anti-estrogen activities [38,39].The acid hydrolysis of these alkaloids yields alkamines [40]. These Glycoalkaloids offer protection to plants against fungi, herbivores, insects, and pests. Interestingly, total glycoalkaloids level (TGA) of 2–5 mg/ kg (body weight) is toxic to humans because, at this level, they produce systemic and gastrointestinal effects and also downregulate acetylcholinesterase’s [41]. These glycoalkaloids produce toxicity by making a complex with sterol of cellular membranes and disrupt cells [42]. Neurological signs and symptoms of toxicity due to glycoalkaloids include; weakness, depression, coma, convulsions, partial paralysis and mental confusion [43]. It has been reported that some glycoalkaloids from Solanum species such as a-solasonine, a-solamargine, and aglycone solasodine show antitumor activity against several tumor cell lines [44]. 3. Aglycone solanidine alkaloids 3.1. Solanine Solanine is a steroidal alkaloid, mostly found in all parts of Solanum nigrum (nightshade). Along with solanine, Solanum

nigrum also contains other steroidal alkaloids such as solasodine i.e. solamargine [45] and solasonine [15]. Solanine was first isolated by Defosses from the leaves of Solanum nigrum in 1820 [46]. Solanine also found in tuber of Solanum tuberosum Linn. [15]. Typically unripe, green and small sized potatoes contain a high amount of solanine as compared to fully ripe and large size potatoes [47]. Its molecular mass is 868 Da [48] (Fig. 2). 3.1.1. Toxic effects of solanine About 0.02% concentration of solanine in potatoes have a toxic effect on humans [46]. The first toxic effect of solanine poisoning was observed in 1932, when a Greek family of eight persons, had a meal of young potatoes shoots and broad beans. At first, there was no sign of toxicity, but after 12 h, symptoms of toxicity revealed, including; headache, colic pain, hot skin, nausea, and vomiting. The other symptoms included weakness, depression, convulsions, diarrhea, abdominal pain and difficulty in breathing [14,47]. In another observation, it was observed that, solanine at a low dose of 200 mg/p.o (per oral) causes itchiness in the neck region, dyspnea, drowsiness, and hyperesthesia. While at higher doses it initiates vomiting and diarrhea. Chemically, solanine has structural resemblance with cardiac glycosides, for this reason, it shows positive inotropic effect [46]. 3.1.2. Antitumor effects of solanine Solanine, at different concentrations, initiates programmed cell death (Apoptosis) in tumor cell lines which include human hepatocarcinoma cell line (HepG2), human gastric carcinoma cell line (SGC-7901) and human large intestine cancer cell line (LS174). The cytotoxic effects of solanine can be observed by measuring different parameters such as morphology, cell cycle phase analysis and rate of apoptosis. In each cell line here, the rate of apoptosis is usually dose dependent. It was observed that HepG2 tumor cells are more sensitive to solanine than other tumor cells. Solanine inhibits the development of HepG2 tumor cells by interfering with S phase of the cell cycle which prevents cells from entering into G2 phase thus prevent cell division. Furthermore, it also inhibits the gene expression of Bcl-2 protein in HepG2 cells and boosts the expression of Bax in HepG2 tumor cells and finally raise Bax/Bcl-2 ratio [15,49]. Bcl-2 family is an anti-apoptotic protein (Mueller, Voigt et al., 2003), mostly localized at the inner

Fig. 2. Chemical structure of a-solanine [42,43,45,111,117].

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mitochondrial membrane, nucleus membrane and membrane of endoplasmic reticulum [50,51]. Bcl-2, with the molar size of 1500 Da, is present in mitochondria and located near to mitochondrial permeability transition (MPT) pores [52], which transport both anionic and cationic molecules [53–55]. Any change in the permeability of these pores results in apoptosis. Bcl-2 prevents any change in permeability of these pores and act as antiapoptotic agent [52]. Bcl-2 also inhibits the release of cytochromeC. Cytochrome-C plays an imperative role in the activation of caspase cascade (cysteine-aspartic-proteases), which is crucial for apoptosis [15]. Solanine also helps in lowering the membrane potential of HepG2 tumor cells in a dose-dependent manner which initiates the opening of mitochondrial permeability transition pores (MPT). The opening of these MPT pores leads to swelling and rupturing of the mitochondrial membrane which releases Ca++ ions from mitochondria into cytoplasm results in high accumulation of Ca++ in the cytosol. These events end in tumor cell death induced by apoptosis [45]. 3.2. Chaconine Saponins are classified as triterpenoids, steroids or steroidal glycoalkaloids (chaconine and solanine) [56], which are present in more than 100 plant species. Chaconine and solanine molecules disrupt cellular membrane and leakage of electrolyte from the cell by forming a complex with plasma membrane sterol at 3b-OH site [57]. The trisaccharide of a-chaconine composed of one glucose and two rhamnose molecules attached to aglycone solanidine moiety at 3-OH position [56]. a-chaconine synthesized in those parts of plants that are naturally bioactive, that is why it offers an environmental protection to plants from fungi, pests, and herbivores. Its molecular weight is 852 Da, and it is ten times more toxic than solanine [38,48]. However, the level of toxicity reduced with the removal of glucose unit from primary structure i.e. gradual elimination of glucose unit from b1-, b2-, g-chaconine

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and solanidine with the order of toxicity b1- chaconine and b2chaconine > g-chaconine > solanidine [56] (Fig. 3). 3.2.1. Anticancer activity of chaconine `Chaconine induces apoptosis by activating caspases-3 and is also responsible for the transfer of phosphatidylserine to plasma membrane; which results in condensation of nuclear chromatin and cytoplasmic contents in human colon carcinoma cells (HT-29). In induction of apoptosis, chaconine is a potent apoptosis inducer than solanine which is due to the presence of side chain glucose molecules attached to the 3-OH position of aglycone solanidine moiety. Chaconine also hampers phosphorylation of ERK-1 (Extracellular signal-regulated kinases-1) to ERK-2 (Extracellular signalregulated kinases-2) [58]. Activated ERK-1 and two signaling pathways are important for cell survival, inhibition of apoptosis, cell motility, cell proliferation, differentiation and metabolism [59–61]. This pathway is simply described as Ras-Raf-MEK-ERK/ MAPK (Ras-Raf-MEK-Extracellular signal-regulated kinases/Mitogen-activated protein kinases) pathway that conveys a signal in response to external stimuli such as growth factor or hormones and regulates gene transcription, which controls several cellular events [62]. When extracellular factors such as paracrine growth factors, autocrine growth factors, and adhesion factors are attached to its receptor e.g. tyrosine kinases (RTK) at the surface of the plasma membrane, it leads to autophosphorylation and dimerization of tyrosine. Phosphotyrosine provides a docking site for growthfactor-receptor bound protein-2 (Grb2) and adaptor protein (Shc). Grb2 drags GDP/GTP exchange factor son of sevenless (SOS) to the plasma membrane, and SOS causes activation of Ras GTPase [63]. Ras is small GTPase present at the membrane, and it has three isoforms i.e. Ha-Ras, N-Ras and Ki-Ras [64]. Ki-Ras isoform is primarily allied with activation of Raf/MEK/ERK signaling pathway; while Ha-Ras isoform activates Pl3K/Akt signaling pathway [60] and N-Ras isoform chiefly linked with the pathogenesis of

Fig. 3. Structure of chaconine and its hydrolysis [56,118].

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melanoma [64]. Ras binding activates and translocates Raf serine/ threonine kinase to the plasma membrane. The Raf consists of three isoforms i.e. A-Raf, B-Raf and Raf-1(C-Raf), these effectors trigger MEK-ERK/MAPK kinase pathway [61,65]. Raf isoforms activate and phosphorylate MEK isoforms MEK-1 and MEK-2 with different potencies i.e. B-Raf > Raf-1 > A-Raf, respectively [65]. Activated MEK, initiates phosphorylation of ERK, following activation shift to nucleus and facilitates the phosphorylation of other transcription factors such as Elk-1, globin transcription factor-1, cAMP response element-binding protein and Fos that hinder apoptosis and after binding with growth factor and cytokine gene, work as a cell growth regulators [64,66,67]. Du et al. [67], also reported that activation of this pathway also upregulates intracellular anti-apoptotic proteins (Fig. 4). 3.2.2. Antimetastasis of chaconine Matrix metalloproteinase (MMPs) family is the endopeptidases that have the zinc-binding capacity [68]. It comprises of 14 members of enzymes divided into four sub-groups i.e. collagenases, gelatinases, stromelysins and the membrane-type MMPs. The over expression of these enzymes degrades most of the components of extracellular matrix (ECM) and therefore, helps in the invasion of tumor cells at different sites and metastasis [69]. There are many MMPs inhibitors available in clinical practice that reduce the expression of MMPs proteins and inhibit tumor cells migration [70]. It was noted that chaconine showed the antimetastatic effects on human lung adenocarcinoma A549 cells by inhibiting the expression of proteolytic enzymes such as of MMPs family (MMP-2 and MMP-9). The expression of MMP-2 and MMP-9 is related to various cellular and physiological events such as cell motility, adhesion, differentiation, proliferation, activation, invasion, growth, and metastasis. The a-chaconine inhibits the actions of MMP-2 and MMP-9 and reduces the migration of human lung adenocarcinoma cells. It inhibits the translocation and binding efficiency of transcriptional factor NF-kB from cytosol to the nucleus and also inhibits the phosphorylation of JNK1/2 and

PI3K/Akt in A549 tumor cells [71]. The inhibition of JNK1/2 and PI3K/Akt signaling pathways and transcriptional factor NF-kB; results in down-regulation of MMP-2 and 9 results in inhibition of cancer metastasis [72] (Fig. 5). 4. Aglycone solasodine alkaloids 4.1. Solamargine Solamargine is of 828 Da molecular weight steroidal glycoalkaloid [73,74]. It is present in nearly 100 Solanum species. Previously, many tumor cells such as lung, hepatoma, breast, prostate, and colon cells were sensitive to solamargine [12]. It has been observed that solamargine also possess hepatoprotective activity against carbon tetrachloride (CCL4) induced hepatotoxicity [75]. At small doses, solamargine initiates apoptosis while at high doses, it causes necrosis. It was found that rhamnose moiety, present in the carbohydrate side chain of solamargine was essential for tumor cell death [76,77] (Fig. 6). 4.1.1. Anticancer effect of solamargine Recently, lung cancer is a primary focus of researchers because lung cancer associated deaths are increasing gradually [78]. Lung cancer is classified into two groups, small cells lung carcinoma (SCLC) and non-small cells lung carcinoma (NSCLC). Type II i.e. NSCLC; constitutes 75–80% of lung cancer and is further subdivided into three subtypes namely adenocarcinoma, squamous cells carcinoma and large cells carcinoma [79]. Previously, Liu et al., [3] reported the cytotoxic effects of solamargine against non-small cell lung carcinoma cell lines (H441, H661, and H520) and small cell lung carcinoma cell line (H69). It was observed that solamargine induces dose-dependent apoptosis by; 1. Increasing binding of tumor necrosis factors (TNFs) to tumor necrosis factor receptors (TNFRs).

Fig. 4. Action of Chaconine on Ras-Raf-MEK-ERK (MAPK) signaling pathway [63].

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Fig. 5. Ras involved in the activation of ERK and PI3K signaling pathway (Downward, 2008).

Fig. 6. Chemical structure of Solamargine [5,110,111,119].

death (apoptosis) and necroptosis (necrosis) [85]. Among all TNF-

2. Downregulation of anti-apoptotic proteins (Bcl-2). 3. Activation of the caspase cascade.

a, TNF-b, CD40L, FasL, TNF-related apoptosis-inducing ligand

Tumor necrosis factor (TNF) is a group or family of cytokines, present as proteins with molecular weights in the range of 40– 70 kDa [80–84]. Human TNFs have a molecular weight of 17 kDa and play a major role in acute and chronic inflammation; cancerrelated inflammation, autoimmune diseases, programmed cell

(TRAIL) and LIGHT are most important [86]. TNFs initiate apoptosis by binding to tumor necrosis factor receptors TNFRs, TNFR-I, and TNFR-II [87]. These receptors are present on different types of cells such as human fibroblasts, endothelial cells, adipocytes, liver membranes and monocytes, different tumor cell lines and hematopoietic cells [88–91]. Their numbers on each cell type

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from 1000–10,000 per cell with affinity constant ranging between 3  10 11 to 2  10 10 M with a molecular weight of 55 kDa (TNFR1) and 75 kDa (TNFR-11) [85,92,93]. These receptors are called death receptors which play a major role in receptor-mediated apoptosis or extrinsic pathway of programmed cell death. When a specific ligand (TNF-a, FasL, TRAIL) comes in contact with death receptors (TNFR1, Fas, TRAIL receptors), the receptors dimerization is initiated. TNFR-1 contains death domains, these death domains (TRADD) interact with FADD (Fas-associated death domain) and help in activation and cleavage of pro-caspase-8 to caspase-8. Caspases-8 causes further cleavage and activation of caspases-3, which induces irreversible programmed cell death or apoptosis [8]. In normal lung cells these receptors are upregulated, but during cancer development, these receptors loss or trim down their response to stimulus or down-regulation of receptors occur [94]. Solamargine induces apoptosis in lung cancer cells by initiating the gene expression of TNFR-I and TNFR-II and also enhances the binding of TNFs to TNFRs. Activation of TNFRs and upregulation of apoptotic TRADD and FADD, during lung cancer, is an important mechanism of action of solamargine and it also boosts the sensitivity of lung cancer cells to TNF-a and TNF-b [3]. Bcl-2 (B-cell lymphoma 2) is encoded by Bcl-2 gene, a founding member of Bcl-2 family of regulatory proteins and shows antiapoptotic and antiproliferative activities. Bcl-2 family comprises of 20 members some of these show antiapoptotic activity (Bcl-2, Bcl-xL, Bcl-w, A1 and Mcl 1) while others show proapoptotic activity (Bax, BH3, and Bid) [95,96] (Fig. 7). Bcl-2 family is an important regulator of the intrinsic pathway of apoptosis [8]. During stress, Bax and Bid relocate in the mitochondrial outer membrane and is responsible for the release of cytochrome-c into the cytoplasm [97–105]. Cytochrome-c along with apoptotic protease activating factor I (Apaf 1), forms apoptosome complex by binding with initiator caspases-9 [106]. This complex activates other caspases such as caspases-3 and 7 which leads to apoptosis [86]. However, upregulation or overexpression of Bcl-2 and Bcl-xL restrains the

release of cytochrome-c from mitochondria, inhibit the Bax and avert the cell death [8,107,108]. It was reported that Solamargine inhibits the expression of Bcl-2 and Bcl-xL and upregulates Bax which causes the release of cytochrome-c and results in apoptosis [8] (Fig. 8). 4.1.2. Cytotoxicity in human hepatic cell line Ding et al., [12] observed the effects of solamargine in human hepatic carcinoma cells line (SMMC-7721, Hep3B), respectively. The solamargine induces apoptosis in a dose-dependent manner by; 1. Arresting the cells at the G2/M phase and induces apoptosis in this cell cycle phase. 2. Activation of caspase-3 3. Initiation or expression of TNF receptors. Kuo et al. [109], found that steroidal glycoalkaloids (solamargine) exert their cytotoxic effects by diffusion into cells, where this molecule irreversibly bounds and activates intracellular receptors that result in transcription of particular genes. 4.1.3. The activity of solamargine against breast cell carcinoma In breast tumor cell lines (HBL-100, SK-BR-3, and ZR-75-1) Solamargine induces apoptosis following extrinsic and intrinsic pathways by shrinking the size, membrane hemorrhage and chromatin condensation of nuclei. The mechanism by which solamargine induces apoptosis in these breast carcinoma cells is similar to other carcinoma cell lines. It has been reported that solamargine induces apoptosis by arresting the cells at G2/M phase of cell cycle through initiating the expression of TNFR, TRADD, FADD and Fas receptors, downregulating of anti-apoptotic proteins Bcl-2 and Bcl-xL, increasing the expression of pro-apoptotic protein Bax, activating caspases 8, 9 and 3 and finally the release of cytochrome-c [8]. It was also reported that solamargine at 2.9 and 7.7 mM concentration produces 50% and 80% cell death in A549 lung

Fig. 7. Bcl-2 related proteins [95].

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Fig. 8. Extrinsic and intrinsic pathways of apoptosis [95].

adenocarcinoma cell line, respectively. Solamargine showed a dose and time-dependent inhibitory effects in these lung cancer cells [74].

mainly due to the presence of glucose moiety in its main structure [10]. Like other glycoalkaloids, solasonine has no inhibitory effects on acetylcholinesterases [37] (Fig. 9).

4.2. Solasonine

5. Solasodine rhamnose glycoside (SRGs)

The Molecular formula of solasonine is C45H73NO16 with a molecular weight of 884.04 Da [110]. Solasonine and solamargine have the same steroidal part, aglycone solasodine but solasonine differs from solamargine at its carbohydrate side chain composition. The trisaccharide of solasonine molecule has a solatriose (Lrhamnopyranose-D-glucopyranosyl-galactopyranose) structure, identical to the corresponding side chain of a-solanine. Hydrolytic elimination of carbohydrate side chain from solasonine, yields solasodine which is readily converted into 16-dehydropregnenolone; an efficient remedy in steroidal medicine [111]. Solasonine exhibits weak antiviral, antifungal, insecticidal and molluscicidal effects [112]. It also shows a concentration-dependent cytotoxicity against human K562 leukemic cells and antiproliferative action against Ehrlich carcinoma cells [113], human colon (HT29) and human liver (HepG2) cancer cells. Cytotoxicity of solasonine is

SRGs are the innovative class of chemotherapeutic agents in which solasodine glycosides, solasonine and solamargine contribute equally. SRGs have the ability to devastate cancer cells due to apoptosis and also show antineoplastic effects with peculiar behavior. The rhamnopyranose component in SRGs binds to specific receptor Endogenous Endocytic Lectins (EELs), present only in cancerous cells as compared to normal cells that’s why SRGs specifically kill cancer cells but imparts no harmful effects on normal healthy cells. Once rhamnose binding glycoprotein is identified and binds to these receptors, it forms SRGs-EELs complex, which internalized into cancer cells through endosomes via receptor-mediated endocytosis. In the cells, SRGs demonstrate anti-mitochondrial and anti-lysosomal activities. Solasodine branch of SRGs ruptures lysosomes. As a result, lysosomal contents (mainly hydrolytic enzymes) released into cytosol that causes the

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Fig. 9. Chemical structure of solasonine [110,112].

death of tumor cells. SRGs trigger apoptosis in cancer cells by increasing the expression of death receptors such as Fas and Fasassociated death domain and TNFR receptors and its death domain. SRGs also decrease the Bcl-2/Bax ratio by downregulating the expression of anti-apoptotic proteins (Bcl-2) and increase the expression of pro-apoptotic proteins (Bax). These outcomes lead the activation of Caspases-8, 9 and 3 in tumor cells. Thus SRGs initiate apoptosis via both extrinsic and intrinsic pathways in cancer cells. SRGs in combination with cisplatin proved more effective against cisplatin-resistant tumor cells, including lung and breast cancer cells [114], as compared to the sensitive phenotypes. Interestingly, it was observed that as a chemotherapeutic agent SRGs are more efficient than Taxol, Cisplatin, Vinblastine, Methotrexate, 5-fluorouracil, Epirubicin, Cyclophosphamide and Gemcitabine [73]. SRGs are commercially available as a topical formulation for the treatment of skin cancer without destroying healthy skin cells [114]. It was first formulated in Australia, licensed in 1991 and marketed as “Curaderm” [115]. Curaderm contains 33% solasonine, 33% solamargine and 34% di- and mono-glycosides, which are present in a topical cream formulation that contains 0.005% glycoalkaloids BEC (a mixture of SRGs). At this low concentration to attain efficacy, keratolytic agents such as salicylic acid (10%) and urea (5%) have to be added to the formulation which assists absorption of BEC to cancer cells. After the application of formulation, keratolytic agents gave slightly burning and stinging sensations, but it has no side effects on liver, kidneys and systemic circulation [116]. 6. Conclusion Studies have shown that steroidal glycoalkaloids, aglycone solanidine (solanine, chaconine) and aglycone solasodine (solamargine, solasonine) have antitumor activity against many tumor cell lines. In many cancer cell lines these compounds trigger apoptosis in two ways, (1) Death receptor-mediated apoptosis (2) Mitochondrial mediate apoptosis. Both depend mainly on the structural modification of carbohydrate moiety attached to aglycone part of these steroidal glycoalkaloids. The molecular

mechanism by these steroidal glycoalkaloid initiates cells death are similar to the currently available chemotherapeutic drugs in clinics. These steroidal glycoalkaloids induce apoptosis by regulating the expression of TNFRs, down-regulating the expression of anti-apoptotic proteins (Bcl-2), increasing the expression of apoptotic proteins (Bax), decreasing the Bcl-2/Bax ratio, disruption mitochondrial and lysosomal membrane and activation of caspases cascade. Furthermore, inhibiting the phosphorylation of ERK1/2, JNK1/2, PI3K/Akt signaling pathways and inhibit the expression of MMPs. According to all these molecular mechanisms of steroidal glycoalkaloids; SRGs (solasodine rhamnose glycoside) formulation was formulated to treat skin cancers successfully. In conclusion, these natural compounds can be a breakthrough for the development of effective chemotherapy in respect of their efficacy and promising specificity. 7. Future directions Concerning the molecular mechanism, toxicity, molecular size and specificity of chemotherapeutic agents; we can suggest some future directions for the development of effective chemotherapeutics. 1. The chemotherapeutic drug should be small enough (<1500 Da) to cross MPT pores. However, for the effective chemotherapy; anticancer agents should be in combination that can help in the reduction of mitochondrial membrane potential. As the membrane potential reduces, MPT pore open and drug gains easy excess to Bcl-2 proteins (anti-apoptotic proteins). 2. At present, most of the tumor cells are resistant to available traditional chemotherapeutics. However, in this case, a combination of drugs is proved to be a promising strategy, such as, when SRGs (solasodine rhamnose glycoalkaloids) are combined with cisplatin it can kill cisplatin-resistant liver and breast cancer cells. Previously, it was concluded that the combinatory drug delivery showed extraordinary effects compared to single drug delivery to treat cancer. 3. Structural modification, presence and a specific length of glucose moiety in the chemical structure of chemotherapeutics

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can be proved more accurate and efficient chemotherapy regimen. 4. The main disadvantage associated with chemotherapy is nonspecificity. Due to this, they can destroy normal healthy cells along with tumor cells. The specific receptors are present on the surface of tumor cells to bind with drugs. So, to achieve specificity, SRGs incorporated formulation should be developed that has potential to bind specifically with EELs, present only on tumor cells. 5. Finally, authors encourage the use of natural compounds as therapeutic agents because of their excellent safety, high efficacy and promising specificity to kill tumor cells.

Authors contribution Abdul Hameed is a Ph.D. student. He contributed to the writing section and prepared the figures of this review. Shakeel Ijaz is a Ph.D. student. He contributed to the writing section of this review. Imran Shair Mohammad is a Ph.D. student. He contributed to the writing section and prepared the figures of this review. He also worked to finalize the manuscript. Kiren Sher Muhammad is a Masters Student. She helped in the literature search. Haji Muhammad Shoaib Khan is an assistant professor. He directed/instructed and guided us to complete this review. Naveed Akhtar is a Professor. He supervised all the work and reviewed the manuscript. Conflict of interest All authors declared no conflict of interest. Acknowledgement The author’s thanks, Dr. Haji Muhammad Shoaib Khan and Dr. Naveed Akhtar for their guidance and support to complete this project. References [1] D. Chanda, S. Bhushan, S.K. Guru, K. Shanker, Z. Wani, B. Rah, S. Luqman, D. M. Mondhe, A. Pal, A.S. Negi, Anticancer activity, toxicity and pharmacokinetic profile of an indanone derivative, Eur. J. Pharm. Sci. 47 (5) (2012) 988–995. [2] S. Nussbaumer, P. Bonnabry, J.-L. Veuthey, S. Fleury-Souverain, Analysis of anticancer drugs: a review, Talanta 85 (5) (2011) 2265–2289. [3] L.-F. Liu, C.-H. Liang, L.-Y. Shiu, W.-L. Lin, C.-C. Lin, K.-W. Kuo, Action of solamargine on human lung cancer cells–enhancement of the susceptibility of cancer cells to TNFs, FEBS Lett. 577 (1) (2004) 67–74. [4] E. Finkel, Does cancer therapy trigger cell suicide? Science 286 (5448) (1999) 2256–2258. [5] L. Sun, Y. Zhao, H. Yuan, X. Li, A. Cheng, H. Lou, Solamargine, a steroidal alkaloid glycoside, induces oncosis in human K562 leukemia and squamous cell carcinoma KB cells, Cancer Chemother. Pharmacol. 67 (4) (2011) 813– 821. [6] J.D. Ly, D. Grubb, A. Lawen, The mitochondrial membrane potential (DCm) in apoptosis; an update, Apoptosis 8 (2) (2003) 115–128. [7] Y. Suárez, L. González, A. Cuadrado, M. Berciano, M. Lafarga, A. Muñoz, F. Kahalalide, A new marine-derived compound, induces oncosis in human prostate and breast cancer cells, Mol. Cancer Ther. 2 (9) (2003) 863–872. [8] L. Shiu, L. Chang, C. Liang, Y. Huang, H. Sheu, K. Kuo, Solamargine induces apoptosis and sensitizes breast cancer cells to cisplatin, Food Chem. Toxicol. 45 (11) (2007) 2155–2164. [9] M.L. de Mesquita, J.E. de Paula, C. Pessoa, M.O. de Moraes, L.V. Costa-Lotufo, R. Grougnet, S. Michel, F. Tillequin, L.S. Espindola, Cytotoxic activity of Brazilian Cerrado plants used in traditional medicine against cancer cell lines, J. Ethnopharmacol. 123 (3) (2009) 439–445. [10] C.C. Munari, P.F. de Oliveira, J.C.L. Campos, S.d.P.L. Martins, J.C. Da Costa, J.K. Bastos, D.C. Tavares, Antiproliferative activity of Solanum lycocarpum alkaloidic extract and their constituents, solamargine and solasonine, in tumor cell lines, J. Nat. Med. 68 (1) (2014) 236–241.

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