Hidden in Plants—A Review of the Anticancer Potential of the Solanaceae Family in In Vitro and In Vivo Studies

Simple Summary The Solanaceae family is one of the most important arable and economic families in the world. In addition, it includes a wide range of valuable active secondary metabolites of species with biological and medical properties. This literature review focuses on the assessment of the anticancer properties of the extracts and pure compounds, and the synergistic effects with chemotherapeutic agents and nanoparticles from various species of the Solanaceae family, as well as their potential molecular mechanisms of action in in vitro and in vivo studies in various types of tumours. Abstract Many of the anticancer agents that are currently in use demonstrate severe side effects and encounter increasing resistance from the target cancer cells. Thus, despite significant advances in cancer therapy in recent decades, there is still a need to discover and develop new, alternative anticancer agents. The plant kingdom contains a range of phytochemicals that play important roles in the prevention and treatment of many diseases. The Solanaceae family is widely used in the treatment of various diseases, including cancer, due to its bioactive ingredient content. The purpose of this literature review is to highlight the antitumour activity of Solanaceae extracts—single isolated compounds and nanoparticles with extracts—and their synergistic effect with chemotherapeutic agents in various in vitro and in vivo cancer models. In addition, the biological properties of many plants of the Solanaceae family have not yet been investigated, which represents a challenge and an opportunity for future anticancer therapy.


Introduction
Cancer is arguably one of the most dangerous diseases for civilization, affecting all people, regardless the their origin, age or social status. Cancer is also one of the most common causes of death after cardiovascular diseases in developed countries. Statistics show that about 20 million new cases were diagnosed in the world in 2020, and as many as 10 million people died as a result of cancer [1]. Apart from the genetic determinants of the development of cancer (e.g., the presence of typical gene mutations), the most common causes of cell transformation are lifestyle factors (e.g., radiation exposure, smoking, poor diet, alcohol consumption, occupational factors or environmental contamination). Gender and age are also of great importance in the development of neoplastic diseases, and have a significant influence on cancer incidence and mortality [2][3][4][5]. Tumour development and progression are complex, involving factors in the cancer cells themselves like abnormally excessive proliferation as well as multidimensional interactions between other cells and tissues in the body. These cells can also cause angiogenesis, and are capable of dividing indefinitely and metastasizing. As such, rapid and correct diagnosis increases the chances of successful treatment [6,7].
Statistics show that one in six deaths in the world today is caused by cancer, and about 70% of these deaths occur in low-and middle-income people [8]. The problem of increased cancer incidence around the world has led to an increasing search for new compounds that are ideally toxic to cancer cells but not to normal cells. As the currently used chemotherapeutic agents show relatively high toxicity towards both neoplastic cells and normal cells [9][10][11], there is great interest in the identification of new compounds of natural origin with specific activity against different cancer types. The anticancer properties of plants have been recognised for centuries. About 60% of the drugs currently used to treat cancer were originally isolated from nature, with the plant kingdom being the most important source. The intensive development of phytochemistry and isolation methods of plant-derived compounds eventually led to the development of a number of anticancer drugs [12].
A considerable variety and number of plants are known to have medicinal properties [13][14][15]. An estimated 70,000 plant species, from algae to trees, have been used for medicinal purposes [16]. The National Cancer Institute (NCI) has studied approximately 35,000 plant species for potential anticancer effects. Among them, about 3000 plant species showed reproducible anticancer activity [8]. While the bioactive principles from these plants can be obtained traditionally by extraction from various natural sources, they can be produced more efficiently using various biotechnological tools. The range of secondary metabolites known to exhibit anticancer properties is chemically broad, with the predominant groups being alkaloids, terpenoids and polyphenols [17,18].
Both pure compounds and extracts of plant origin show cytotoxic effects by inducing apoptosis in cancer cells [19][20][21][22][23][24]. Secondary metabolites, either used per se or as nanoparticles in targeted therapy, have also been found to have numerous effects on cancer, both in vitro and in vivo; they also appear to interact with chemotherapeutic agents, thus positively or negatively affecting their efficacy, and to protect normal cells against the adverse effects of anticancer therapies [25][26][27].
One family of plants commonly included in the diet is the Solanaceae. It is one of the largest plant families, and its genus-Solanum-is the richest in edible species, including potatoes (Solanum tuberosum), tomatoes (Solanum lycopersicum) and eggplants (Solanum melongena); in addition, peppers are widely-consumed vegetables which are included in the related genus Capsicum [28,29]. The Solanum genus contains a range of phenolic, alkaloid, saponin, terpene and lipid compounds; as such, it has frequently been used for medicinal purposes. Many of the alkaloids from the Solanum genus are particularly interesting because they

Medicinal Plants in Cancer Treatment
Phytotherapy is believed to have originated with the Sumerian and Chinese civilizations over four thousand years ago, and became particularly prominent in ancient Egypt. The first plant to be used against cancer may have been Trifolium pratense: Dioscurides reported its use in the treatment of neoplasms in De Materia Medica, together with an extract of Colchicum autumnale known to have anticancer properties, which were attributed to its colchicine content. Elsewhere, Avicenna also mentions the use of Ricinus communis, Atropa belladonna, Urtica dioica, Narcissus poeticus, Scrophularia nodosa and Ecbalium elaterium. Currently, the rapid development of phytochemistry has allowed the discovery of Plant compounds generally suffer from low bioavailability and hydrophobicity issues, which have been addressed with the use of recently discovered nanomaterials, many of which may also be of natural origin. Nanoparticle application has led to the increase of the concentration of the drug in neoplastic cells with particular receptors on their surface [70][71][72][73][74]. A nanoparticle consists of a drug on the inside, and a so-called "ligand"i.e., a molecule designed to bind to a tumour cell receptor-on the outside. After binding to the receptor, the nanoparticles are absorbed into the cell and the drug is released. Compounds of plant origin (pure compounds or extracts) have been used in combination with nanoparticles and with chemotherapeutic agents in adjunctive therapies [75,76].
However, it should be noted that plant preparations have more complicated and unpredictable interactions with drugs than would be expected between two conventional drugs due to the numerous active compounds found in the plant raw materials. This may be due to the fact that compounds of plant origin may influence the pharmacokinetics and pharmacodynamics of the anticancer drugs used. As a consequence, toxic drug effects may be observed or treatment efficacy may be reduced [77][78][79][80]. So far, numerous studies have highlighted the positive effects deriving from the co-administration of drugs with plant extracts. For example, Hussain et al. reported a synergistic effect between cisplatin and Aloe vera extract on MCF-7 and HeLa cancer cell lines, suggesting that the plant extract may increase the therapeutic efficacy of conventional anticancer drugs [81]. In addition, Senna obtusifolia extract was found to have a synergistic effect in combination with doxorubicin [43].

Nanotechnology and Plant Compounds in the Fight against Cancer
The advance of modern technology has brought new products and research techniques which have driven significant scientific progress. Nanotechnologies have successfully entered everyday life, and are increasingly used in medical sciences. Many common devices are based on the achievements of modern nanotechnology, such as energy-efficient and powerful electronic devices, versatile nanocoatings, and new-generation cosmetics [82][83][84]. In its simplest definition, nanotechnology is a "nano-scale technology", i.e., a technology in the size range 1-100 nm. For a better understanding of these sizes, the nanometer scale (nm) is one billionth of a meter, or three to five atoms wide: less than one tenth of a micrometer in at least one dimension.
The latest scientific achievements may turn out to be effective treatments for diseases that have been troubling people for centuries, among which cancer is still a challenging and often unresolved issue. In the past, the detection of neoplastic diseases was possible only after the appearance of specific symptoms, generally in an advanced stage of the disease, and even in the presence of distant metastases. A more complete view of pathologicallychanged tissues can be obtained by biopsy; however, this method has many limitations, and carries the risk of complications [85,86]. In response, highly-sensitive non-invasive methods of detecting neoplastic diseases have been developed, most of which rely heavily on nanotechnology [87].
In fact, nanomaterials are widely used in the diagnosis and treatment of different types of cancer due to the possibility of precisely controlling their shapes, sizes and specific physical properties. Nanoparticles can also serve as carriers of anticancer drugs to specific cells [88], and nanomaterial-based devices used to detect the proteins or nucleic acids of cancer cells can provide an early indication of disease or monitor the effectiveness of therapy. Such biomarkers can be detected in body fluids such as blood, saliva and urine. One such group of tumour biomarkers are proteins. A number of biomarkers are routinely tested in clinical practice-PSA (prostate cancer), CEA (colorectal cancer), CA-125 (ovarian cancer), ER (breast cancer), AFP (liver cancer) and CA 19-9 (pancreatic cancer)and nanosensors can be successfully used to detect them [89][90][91][92][93][94]. The most frequently used nanoparticles in the diagnosis of cancer diseases are gold nanoparticles, nanoshells and quantum dots [95,96]. Nanoparticles such as micelles, dendrimers, quantum dots, liposomes and carbon nanotubes can also be used in the treatment of neoplastic diseases. Traditional chemotherapeutics include alkylating agents and antibiotics that induce damage to the DNA of cancer cells. Topoisomerase or mitosis inhibitors are also used [97]. Many of these therapeutics are highly effective, but they often demonstrate a lack of specificity, resulting in severe side effects [98]. There is a clear need for new methods allowing for the effective and specific targeting of neoplastic cells. One potential strategy that has received much attention over the past few years involves the use of nanoparticles [99][100][101], as well as those based on a combination of modern nanotechnology with a rich arsenal of compounds of natural origin with anticancer properties [102][103][104][105][106].
The nanoparticles themselves are typically obtained by electrospraying, evaporationcondensation, laser ablation or pyrolysis, or high-energy ball milling. They can also be obtained chemically by chemical vapor synthesis, the sol-gel method, hydrothermal synthesis, microemulsion technique, or polyol synthesis [107,108]. It is worth emphasizing that physical methods sometimes have an advantage over chemical methods due to the lack of danger of solvent contamination in the prepared thin films, and due to the uniformity of the synthesized nanoparticle distribution [109]. However, these synthesis methods are often complicated and require strictly controlled temperature, pH and pressure conditions, as well as specialized equipment, and often environmentally-hazardous reagents containing heavy metals [110]. Hence, many research teams are interested in the biological synthesis of nanoparticles, which should offer weak contamination with toxic agents, the customization of desired properties, repeatability and easy scalability [111,112].
Among the various biological systems used for this purpose, plants deserve special attention because plant cells may contain a wide range of bioactive compounds with potential anticancer properties. One study examined the antitumour potential of Nepeta deflersiana extract in silver nanoparticles (ND-AgNPs) against human cervical cancer (HeLa) cells, as well as the influence of cytotoxic concentrations of ND-AgNP on markers of oxidative stress, reactive oxygen species (ROS) production, mitochondrial membrane potential, cell cycle arrest, and apoptosis/necrosis. It was found that the cytotoxicity of the tested particles was concentration dependent, and that the treatment was associated with a significant increase in ROS and lipid peroxidation, and a decrease in matrix metalloproteinases (MMPs) and glutathione levels. The cell cycle analysis and apoptosis/necrosis assay data showed that ND-AgNP induced SubG1 arrest and apoptotic/necrotic cell death [113]. Gomathi et al. examined the potential for silver nanoparticles to be biosynthesized in the fruit shell of Tamarindus indica. Here, too, the plant extract acts as a reducing and stabilizing agent for silver nanoparticles. These nanoparticles proved to be cytotoxic to MCF-7 cell lines; hence, they could be considered as potential therapeutic agents in the treatment of human breast cancer [114].
Because plants from the Solanaceae family produce a number of compounds with proven or potential anticancer activity, they may well be used on a large scale as the basis for new systems for the biosynthesis of nanoparticles exhibiting anticancer activity. Combined with the extremely rapid technological progress, this may be the starting point for the development and implementation of completely new and more effective methods of fighting cancer. The general scheme of the synthesis and application of nanoparticles in cancer diagnosis and treatment is presented in Figure 2.
for new systems for the biosynthesis of nanoparticles exhibiting anticancer a bined with the extremely rapid technological progress, this may be the star the development and implementation of completely new and more effectiv fighting cancer. The general scheme of the synthesis and application of na cancer diagnosis and treatment is presented in Figure 2.

Synergy between Chemotherapeutic Agents and Plant Compounds in C Therapy
Despite its many side effects, chemotherapy remains the most popular cancer. Although many chemotherapeutic compounds are of plant origin (e camptothecin, colchicine, vincristine, and podophyllotoxin, etc.), being eithe

Synergy between Chemotherapeutic Agents and Plant Compounds in Cancer Therapy
Despite its many side effects, chemotherapy remains the most popular treatment for cancer. Although many chemotherapeutic compounds are of plant origin (e.g., paclitaxel, camptothecin, colchicine, vincristine, and podophyllotoxin, etc.), being either synthetic or isolated directly from plants, they have considerable side effects. Moreover, their low water solubility, poor penetration into target cells, limited therapeutic potential and toxic side effects may limit the suitability of these natural agents for the treatment of cancer [9,11,63,[115][116][117]. Therefore, new phytochemical anticancer agents require substantial evidence of efficacy from appropriate preclinical trials before their approval for use in patients [79,[118][119][120][121]. It is also possible to chemically modify the molecule and improve its properties [122].
One new therapeutic strategy which is based on the synergistic action between chemotherapeutic agents and plant compounds intends to overcome these shortcomings. Synergy comes from the Greek word "synergos", which means "working together", and is broadly defined as the interaction of two or more compounds or other factors to produce a combined effect greater than the sum of their separate parts [123,124]. Synergistic effects are believed to arise from synergistic multi-target effects, the modulation of pharmacokinetic or physicochemical effects, interference with resistance mechanisms, or elimination and neutralization potentials [125][126][127][128]. Studies show that a secondary compound or plant extract-such as essential oil derivatives, polyphenol derivatives or terpenoid derivatives-may be capable of removing or neutralizing the toxic effects or side effects of a drug [123,[129][130][131].

Solanaceae Family-General Characteristics and Application
The Solanaceae (nightshades) are considered to be the third most economically-important family in the plant kingdom after the Poaceae and the Fabaceae. They are also one of the most significant families of trees, shrubs and herbs, with great floristic, phytochemical and ethnobotanical importance, with over 90 genera comprising 3000-4000 species spread all over the world. Almost half of these belong to the large and varied genus Solanum. It is distributed in all continents except Antarctica, with the greatest diversity being observed in Central and South America [132][133][134][135][136]. In addition to Solanum, the leading genera of the Solanaceae family include Atropa, Datura, Capsicum, Nicotiana, Lycium, Hyoscyamus, Lycopersicon, Withania and Petunia. This single-genus hyper-diversity is remarkable in angiosperms, making Solanum interesting from an evolutionary point of view, as well as for its usefulness to humans ( Figure 3).

Solanaceae Family-General Characteristics and Application
The Solanaceae (nightshades) are considered to be the third portant family in the plant kingdom after the Poaceae and the Faba of the most significant families of trees, shrubs and herbs, with gre ical and ethnobotanical importance, with over 90 genera compri spread all over the world. Almost half of these belong to the large num. It is distributed in all continents except Antarctica, with the observed in Central and South America [132][133][134][135][136]. In addition t genera of the Solanaceae family include Atropa, Datura, Capsicum, cyamus, Lycopersicon, Withania and Petunia. This single-genus hyp ble in angiosperms, making Solanum interesting from an evoluti well as for its usefulness to humans ( Figure 3).  The representatives of the Solanaceae vary extremely in regards to their habit, distribution and morphology, with an astonishing variety of flowers and fruits. The flowers are usually radially symmetrical, with five united sepals, five united petals, five stamens inserted on the tube. The ovary is positioned superior. It consists of two united carpels with the partition walls often present, but more obvious in wild species than domestics. The leaves are alternate, or rarely opposite, and are usually simple. The fruit is a two-chambered capsule called a berry [28,29,[137][138][139][140][141][142][143]. In addition to a wide range of other uses (e.g., traditional medicine, traditional culture, pharmacology, and ornamental horticulture), the species of the Solanaceae are of great importance as food crops around  [29,142,143] The Solanaceae are also known to possess a diverse range of biologically-active compounds that can be used to benefit human health, such as phenolics, alkaloids, saponins, terpenes and lipids. However, toxic alkaloids such as tropane alkaloids or glycoalkaloids are of particular interest because of their reported antimicrobial, anti-rheumatic and antioxidant activities [145]. They have also demonstrated antitumour activity against several types of cancer, including prostate, breast and colon cancer [146,147]. Tropane alkaloids such as atropine, hyoscyamine and scopolamine have a characteristic bicyclic structure, and particularly high concentrations have been found in Datura stramonium, Datura ferox and Datura innoxia. Atropine is a racemic mixture of two enantiomeric forms of hyoscyamine, with the L-enantiomeric form being the active one. Scopolamine, which acts as an antagonist at both the peripheral and central muscarinic receptors, is the most valuable member of a group known as the tropane alkaloids [143,147,148]. This group is highly diverse, being formed from a tropane skeleton, which is highly prone to modification. Tropane alkaloids are found in all plant parts, with the highest concentrations in roots and seeds. Their levels vary according to their species, season, location, and plant organ. From a pharmacological standpoint, they are well known as potent anticholinergic agents, meaning that they inhibit neurological signals from the endogenous neurotransmitter acetylcholine. The symptoms of an overdose may include a dry mouth, ataxia, dilated pupils, convulsions, urinary retention, hallucinations, coma, and death [140,147,149].
Glycoalkaloids are produced in more than 350 plant species, particularly those of the Solanaceae and Liliaceae families. They are a group of glycosidic derivatives of nitrogencontaining steroids consisting of a cholestane skeleton with a carbohydrate moiety of one to five monosaccharides attached at the 3-OH position [150]. Arguably, the most significant glycoalkaloids are α-solanine and α-chaconin, which are contained in potatoes (Solanum tuberosum); solasonin and solamargine, in eggplants (Solanum melongena); and α-tomatin and dehydrotomatin, which are spirosolan-type glycoalkaloids found in tomato plants (Lycopersicon esculentum) [151].

Anticancer Effect and Potential Mechanisms of Action of Plant Extracts from the Solanaceae Family
Thanks to their wide range of active substances, plant extracts exert a variety of effects on cancer cells, with some of them having been reported to have inhibitory effects on cell proliferation [152]. Indeed, a number of in vitro and in vivo studies have found extracts from Solanaceae family members to also have strong anticancer properties.
In the Solanum genus, a Solanum lycopersicum leaf extract was shown to exhibit potential antitumour properties against breast cancer cells by modulating the expression of genes associated with cancer growth and progression [153]. In addition, a Solanum lyratum extract taken from the whole plant exhibited a proapoptotic effect against human osteosarcoma epithelial cells. The apoptosis induction took place through a number of routes: the increase of reactive oxygen and nitrogen species production; the decrease of mitochondrial membrane potential; the release of cytochrome c; the activation of caspase 3, 8 and 9; the increase of the level of proapoptotic proteins, including Bax; and the decrease of the level of anti-apoptotic proteins, including Bcl-2 [154]. Solanum nigrum fruit extract has also been found to decrease viability by the induction of apoptosis and cell cycle arrest at the G2/M phase in prostate cancer cells [155], and to inhibit the proliferation, migration and invasion of glioma cells by the induction of their apoptosis [156].
Extracts of Withania species are also indicated to have specific cytotoxic properties against cancer cells. Withania somnifera leaf extract was found to have cytotoxic effects against human osteosarcoma, fibrosarcoma and lung cancer epithelial cells, and to activate tumour suppressor proteins including p53 [157]. Similarly, extracts from different parts of Withania coagulans were found to bestow antiproliferative properties and NFκB pathway induction [158].
In addition, Capsicum annuum seed extract has been shown to inhibit the migration of lung cancer and breast cancer cells by downregulating metalloproteinases MMP-2 and MMP-9, and increasing E-cadherin expression [159]. Furthermore, leaf and shoot extracts of Nicotiana glauca exhibit cytotoxic properties against lung cancer and prostate cancer cells, and demonstrate anti-angiogenic properties in vivo by inhibiting microvessel formation [160].
Recent reports on the anticancer properties of plant extracts in the Solanaceae family are listed in Table 1.  Cytotoxic (IC 50 values in the range of 40-80 µg/mL); induction of apoptosis (in extrinsic-and intrinsic-dependent pathways) by changing levels of the proteins p21, p16, CDK2 and CDK6, and cyclins D1 and E. It also promotes proapoptotic proteins Bax and Bad and inhibits anti-apoptotic proteins Bcl-2 and Bcl-xl, promotes ROS and Ca2þ production, decreases mitochondrial membrane potential, increases NO production [192] Solanum nigrum L. whole plant water alkaloids, glycosides, flavonoids, polyphenols terpenoids, and saponins

Anticancer Effect and Potential Mechanisms of Action of Pure Compounds Isolated from the Solanaceae Family
Although plants and natural extracts are very important sources of biologically-active compounds, the study of their isolated products can provide a starting point for the development of new drug candidates with unique structures and mechanisms of action. Indeed, many of the secondary metabolites produced by the Solanaceae have been found to be of medical importance, with effects on cancer cells [13].
For example, solajiangxins H, solajiangxins I and 7-hydroxylsolajiangxin I isolated from whole plant extracts of Solanum lyratum show cytotoxic effect against intestinal cancer cells [213]. Solanum aculeastrum, containing steroidal glycosides, showed antitumour activity against various cancer cell lines, including lung, colon and cervical cancer cells [214]. In turn, Shieh et al. demonstrated the time-and dose-dependent inhibition of cell viability in α-tomatine-treated non-lung cancer cells [215]. The steroidal alkaloid soladulcidine, isolated from Solanum dulcamara, and ten of its derivatives were shown to have significant antiproliferative effects against prostate cancer cells [216]. In addition, 35 withanolides and withaferin A from the roots and leaves of Withania somnifera have demonstrated efficacy against a wide range of cell lines [217,218]. Withawrightolide and four other withanolides derived from the aerial parts of Datura wrightii were similarly found to exhibit cytotoxic properties against glioma cells [219]. In addition, Physalis peruviana seed extract induced apoptosis in HeLa cells [220].
In particular, secondary metabolites of the Solanaceae family are known to induce apoptosis in various types of cancer cells by activating different signalling pathways. These differences may result from both chemical structure of the compounds and specific sensitivity of cancer cells. Such compounds with antiproliferative properties commonly affect processes associated with the cell cycle, gene expression, signal transduction pathways, changes in the mitochondrial membrane, metabolic pathways, and autophagy [31].
The cell cycle is an important mechanism that determines cell proliferation. Alkaloids such as baimantuoluoamide A and baimantuoluoamide B inhibit cyclin-dependent kinase 4 (CDK4) activity, and glycoalkaloids such as solasonine, solanidine, and solamargine induce cycle arrest in the S phase. Arrest in the G2/M phase is induced by solamargine and withaferin A [24]. Withaphysalin F-isolated from the leaves of Acnistus arborescens-also has anti-proliferative properties and the ability to arrest the cell cycle in the G2/M phase, which has been attributed to the inhibition of tubulin polymerization and the induction of DNA fragmentation [221].
The compounds also influence gene expression. For example, withaferin A is known to inhibit transcription factors such as MYB and C/EBPβ [31]. In addition, solasonine, β1solasonine, solamargine and solanigroside P isolated from the aerial part of Solanum nigrum show antiproliferative properties against gastric cancer cells, and can induce apoptosis by altering gene expression, such as by increasing Bax expression, decreasing Bcl-2 expression, and activating caspase-3 [222]. Lycopene, a carotenoid found commonly in Solanum lycopersicum, was found to regulate the expression of various apoptosis-related proteins and genes-such as caspase-3, caspase-8, Bax, Bax:Bcl-2 and Bcl-xL-among breast cancer cells [223]. Furthermore, physalin F derived from the whole plant Physalis minima has cytotoxic effects and induces the apoptosis of breast cancer cells through caspase-3 activation and DNA fragmentation [224]. In turn, solamargine increased the expression of p53, Bax and Bcl-2 in U2OS and K562/A02 cells on the mRNA and protein levels, and the mRNA expression and promoter activity of EP4, as well as the protein expression of SP1 and NF-κB subunit p65 in lung cancer cell lines [225].
In addition, they can also inhibit various signalling pathways that may be responsible for cell growth and proliferation. For example, withanolide S5 inhibits receptor tyrosine kinases, withametelin and coagulansin A downregulate the Mitogen-Activated Protein Kinase (MAPK) pathway and the phosphatidylinositol-3-kinase (PI3K) pathway, and 4βhydroxywithanolide E targets the Wnt/β-catenin pathway. Solamargine suppresses the phosphorylation of Akt [225]. In addition, withaferin A inhibits colon cancer by inhibiting Notch-1 signalling, as indicated by the downregulation of Notch-1 targets including Hes-1 and Hey-1; it also inhibits its cross-talk with the Akt/mTOR pathway, thus suggesting the Notch-Akt-mTOR axis as a therapeutic target in colon cancer [226]. Furthermore, αchaconine and α-solanine reduce the expression and activity of the Akt and ERα signalling pathways in human endometrial carcinoma cells [227]. In addition, arabinogalactan upregulates two of the three MAPK cascades, including c-jun N-terminal kinase (JNK) and p38 kinases, and downregulates the third based on extracellular signal-regulated kinases (ERK), and scopoletin demonstrates a strong binding affinity with vascular endothelial growth factor (VEGFA), which is involved in signalling [31].
Solanaceae-isolated compounds may also induce apoptosis by influencing the mitochondrial membrane. Defensin (NoD173), for example, permeates the mitochondrial outer membrane, resulting in the potential collapse of the membrane, followed by the release of cytochrome c and the activation of caspases. In turn, α-solanine was found to induce mitochondrial mediated apoptosis by opening pores and inducing the release of cytochrome c and Smac from mitochondria into the cytosol, further activating caspase-9 and decreasing the mitochondrial membrane potential [228].
They may also alter metabolic pathways: physapubescin I blocks kidney-type glutaminase, an enzyme involved in ATP production. Its downregulation may inhibit the growth and proliferation of cancer cells. Finally, physapubescin B is known to activate autophagy via mTORC1 inhibition, while physapubenolide downregulates key proteins involved in the process [31].
Recent reports on the anticancer properties of pure compounds isolated from plants from the Solanaceae family are listed in Table 2.
The mechanisms of action described in the text and included in Table 2 are presented in Figure 4. phosphorylation of Akt [225]. In addition, withaferin A inhibits colon cancer by inhibiting Notch-1 signalling, as indicated by the downregulation of Notch-1 targets including Hes-1 and Hey-1; it also inhibits its cross-talk with the Akt/mTOR pathway, thus suggesting the Notch-Akt-mTOR axis as a therapeutic target in colon cancer [226]. Furthermore, αchaconine and α-solanine reduce the expression and activity of the Akt and ERα signalling pathways in human endometrial carcinoma cells [227]. In addition, arabinogalactan upregulates two of the three MAPK cascades, including c-jun N-terminal kinase (JNK) and p38 kinases, and downregulates the third based on extracellular signal-regulated kinases (ERK), and scopoletin demonstrates a strong binding affinity with vascular endothelial growth factor (VEGFA), which is involved in signalling [31]. Solanaceae-isolated compounds may also induce apoptosis by influencing the mitochondrial membrane. Defensin (NoD173), for example, permeates the mitochondrial outer membrane, resulting in the potential collapse of the membrane, followed by the release of cytochrome c and the activation of caspases. In turn, α-solanine was found to induce mitochondrial mediated apoptosis by opening pores and inducing the release of cytochrome c and Smac from mitochondria into the cytosol, further activating caspase-9 and decreasing the mitochondrial membrane potential [228].
They may also alter metabolic pathways: physapubescin I blocks kidney-type glutaminase, an enzyme involved in ATP production. Its downregulation may inhibit the growth and proliferation of cancer cells. Finally, physapubescin B is known to activate autophagy via mTORC1 inhibition, while physapubenolide downregulates key proteins involved in the process [31].
Recent reports on the anticancer properties of pure compounds isolated from plants from the Solanaceae family are listed in Table 2.
The mechanisms of action described in the text and included in Table 2 are presented in Figure 4.

Anticancer Effect and Potential Mechanisms of Action of Nanoparticles in Combination with Plant Extracts from the Solanaceae Family
Plant-based nanomaterial synthesis has been growing in popularity. The approach is more environmentally friendly than chemical or physical methods, and many studies have reported that it yields nanoparticles with improved pharmacological properties [277]. Regarding extracts from the Solanaceae, the available data indicate that silver nanoparticles generated by Datura inoxia exert significant antiproliferative effect against lung cancer cells. They also induce apoptosis cell cycle arrest and inhibit DNA synthesis [278]. Recent reports on the anticancer properties of nanoparticles using extracts from the Solanaceae family are listed in Table 3. Table 3. Anticancer effect of nanoparticles in combination with plant extracts from the Solanaceae family, and their potential mechanisms of action. Cytotoxic (MTT test); induction of apoptosis by changes in expression of proliferation-and apoptosis-related genes (overexpression Baxḑ own-regulation Bcl-2), and activation of caspases 3 and 9

Synergistic Effect of Chemotherapeutic Drugs and Plant Extracts from the Solanaceae Family
The occurrence of drug resistance indicates the need to search for new chemotherapeutic agents and improved combinations of them. Combined anticancer therapy uses drugs that target different pathways, as this can result in improved cytotoxicity for the cancer cell, with both additive and synergistic effects [293]. Synergy can also be observed between conventional drugs and chemical compounds and extracts, and some plant-derived compounds have been found to improve the effeciency of anticancer therapy [124]. For example, Solanum nigrum leaf extract has been found to enhance the effect of cisplatin, doxorubicin, docetaxel and 5-fluorouracil, resulting in the induction of intestinal cancer cell autophagy through the accumulation of microtubule-associated proteins [294]. Moreover, whole-plant Solanum nigrum extract has intensified the effect of doxorubicin in the suppression of the growth of HeLa [295] and breast cancer cells [296]. Recent reports on the synergistic properties of extracts from the Solanaceae family and anticancer drugs are listed in Table 4.

Anticancer Effect in In Vivo Studies of Compounds of the Solanaceae Family
Due to due to their high content of bioactive compounds, Solanaceae family members have also been used in a number of in vivo studies. This review categorizes in vivo studies as extracts, pure compounds, nanoparticle extracts and chemotherapeutic extracts. For example, Wu et al. showed that SR-T100-extracted from Solanum incanum (solamargine alkaloid)-caused all papillomas (35/35) and 27 of the 30 UVB-induced microinvasive squamous cell carcinoma in hairless mice to disappear within 10 weeks of the daily use of topical SR-T100 [304]. In other studies, Wu et al. found that Solanum incanum extract (SR-T100) paclitaxel and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts, compared to the vehicle control, and that the combination of cisplatin and SR-T100 was more effective than either treatment alone. The authors suspect that SR-T100 may represent a potential therapeutic adjunct to chemotherapy for ovarian cancer treatment [300]. Furthermore, Solanum lyratum aerial part extract was found to significantly inhibit the growth of S180 sarcoma in mice in vivo, and to increase the proliferation of splenocytes, natural killer cells and cytotoxic T cells, as well as interleukin 2 and interferon-γ, by splenocytes. The authors propose that the extract exhibits its anti-tumour effects through its immunomodulatory properties [305]. Solasodine and rhamnosyl glycosides isolated from Solanum sodomaeum were found to demonstrate antitumour properties in a mouse model [306].
In turn, Deng et al. revealed that the fraction from Lycium barbarum polysaccharide could reduce immunotoxicity and enhance the antitumour activity of doxorubicin in mice. The results showed that Lycium barbarum polysaccharide did not protect against the bodyweight loss caused by doxorubicin, but it promoted the recovery of bodyweight starting at day 5 after doxorubicin treatment in tumour-free mice. Lycium barbarum polysaccharide also improved peripheral blood lymphocyte counts, promoted cell cycle recovery in bone marrow cells, and restored the cytotoxicity of natural killer cells. Furthermore, in H22 tumour-bearing mice, Lycium barbarum polysaccharide enhanced the antitumour activity of doxorubicin, and improved the peripheral blood lymphocyte counts and the cytotoxicity of splenocytes [307]. Diwanay et al. noted that the alkaloid-free polar fraction of Withania somnifera resulted in protection towards cyclophosphamide-induced myelo-and immunoprotection, as was evident from the significant increase in white cell counts and hemagglutinating and hemolytic antibody titers. Treatment with these candidate drugs may be important in the development of adjunctive therapy with anticancer chemotherapy [308].
The anticancer and radio-sensitizing efficacy of a Withania somnifera extract/Gadolinium III oxide nanocomposite (WSGNC) was also investigated in mice. WSGNC treatment combined with γ-radiation led to a significant decrease in the solid Ehrlich carcinoma size and weight in mice; this was associated with a significant decrease in mitochondrial enzyme activities, glutathione content and superoxide dismutase (SOD) activity, as well as a significant increase in caspase-3 activity, malondialdehyde concentration and DNA fragmentation in cancer tissues. The authors indicate that WSGNC can be considered as a radio-sensitizer and an anticancer modulator, suggesting a possible role in the reduction of the radiation exposure dose during radiotherapy [309]. Further studies are presented in the Table 5.  Solanum lycopersicum L. different parts -α-tomatine Intraperitoneally administered α-tomatine (5 mg/kg body weight) also markedly inhibited growth of the tumour using CT-26 cancer cells without causing body and organ weight changes. The reduced tumour growth in the BALB/c mice by 38% after 2 weeks was the result of increased caspase-independent apoptosis associated with increased nuclear translocation of AIF and decreased surviving expression in tumour tissues. [260] Solanum nigrum L. fruits methanol rutin, solasonine, quercetin and solamargine Reduction of the growth and infiltration of C6 glioma tissue and suppressed the proliferation of tumour cells in Wistar rats brain [311] Solanum nigrum L. stems -polysaccharide fraction (SN-ppF3) Tumour suppression mechanisms observed in SN-ppF3-treated mice were most probably due through enhancing the host immune response [312] Solanum nigrum L. leaves -uttroside B Drastic inhibition of tumour growth produced by uttroside B in NOD-SCID mice bearing human liver cancer xenografts demonstrates the chemotherapeutic efficacy of uttroside B [268] Solanum nigrum L. --degalactotigonin Degalactotigonin injected intraperitoneally after tumour inoculation, significantly decreased the volume of osteosarcoma xenografts in athymic nude (nu/nu) mice model and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs [269] Withania somnifera L. leaves water ASH-WEX extract Reduced the intracranial tumour volumes in vivo and suppressed the tumour-promoting proteins p-nuclear factor kappa B (NF-κB), p-Akt, vascular endothelial growth factor in the albino rat model of orthotopic glioma allograft [211]

Conclusions and Future Perspectives
Cancer is a devastating disease, and the currently available treatments for patients are generally associated with undesirable adverse effects. The use of medicinal plants to manage or arrest the carcinogenic process provides an additional strategy that can be used alongside treatments with canonical drugs. Many plant-derived bioactive compounds have achieved favorable results in clinical studies, and their tumouricidal properties against various cancers are under investigation.
This literature review evaluated the anticancer properties of natural products from the Solanaceae family. They were grouped in terms of extracts, pure compounds, nanoparticles with extracts, and chemotherapeutic agents with extracts, and their potential mechanisms of action were given. Although all of the studies found the extracts to demonstrate strong in vitro and in vivo anticancer activity in cancer cell lines and animal models, more research is needed in order to elucidate their specific mechanisms of action, and to determine their potential for cancer prevention and treatment.
Plants of the Solanaceae family are widely discussed due to their multi-directional activity. Multiple in vitro studies have been reported with promising results. On the other hand, the anti-tumour potential of the secondary metabolites from Solanaceae is also quite clear. In addition, nanotechnology techniques can enhance their action and eliminate negative effects on normal cells. Thus, plants of the Solanaceae family should be tested further in order to better elucidate their therapeutic potential not only in in vitro and in vivo studies but also in clinical applications. However, the study of these plants should not limit the study of the plethora of anticancer plants, some of which are still unexplored. Research is needed in order to elucidate the antitumour mechanism of action of many already studied and unexplored plants.

Conflicts of Interest:
The authors declare no conflict of interest.