BioMed Research International

BioMed Research International / 2015 / Article
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Antimicrobial Peptides: Current and Potential Applications in Biomedical Therapies

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Review Article | Open Access

Volume 2015 |Article ID 735087 |

Jaquelina Julia Guzmán-Rodríguez, Alejandra Ochoa-Zarzosa, Rodolfo López-Gómez, Joel E. López-Meza, "Plant Antimicrobial Peptides as Potential Anticancer Agents", BioMed Research International, vol. 2015, Article ID 735087, 11 pages, 2015.

Plant Antimicrobial Peptides as Potential Anticancer Agents

Academic Editor: Dennis K. Bideshi
Received01 Aug 2014
Revised25 Sep 2014
Accepted26 Sep 2014
Published01 Mar 2015


Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms and are promising candidates to treat infections caused by pathogenic bacteria to animals and humans. AMPs also display anticancer activities because of their ability to inactivate a wide range of cancer cells. Cancer remains a cause of high morbidity and mortality worldwide. Therefore, the development of methods for its control is desirable. Attractive alternatives include plant AMP thionins, defensins, and cyclotides, which have anticancer activities. Here, we provide an overview of plant AMPs anticancer activities, with an emphasis on their mode of action, their selectivity, and their efficacy.

1. Introduction

Cancer is a leading cause of death worldwide. In 2012, cancer caused 8.2 million deaths, and cancers of the lungs, liver, colon, stomach, and breast are main types [1]. A hallmark of cancer is the rapid growth of abnormal cells that extend beyond their usual limits and invade adjoining parts of the body or spread to other organs, a process known as metastasis. Cancer treatment requires careful selection of one or more therapeutic modalities, such as surgery, radiotherapy, or chemotherapy. Despite progress in anticancer therapies, the chemotherapeutic drugs used in cancer treatment have the serious drawback of nonspecific toxicity. Additionally, many neoplasms eventually become resistant to conventional chemotherapy because of selection for multidrug-resistant variants [2]. These limitations have led to the search for new anticancer therapies. An attractive alternative is the use of antimicrobial peptides or AMPs, which represent a novel family of anticancer agents that avoid the shortcomings of conventional chemotherapy [3].

AMPs are amphipathic molecules produced by a wide variety of organisms as part of their first line of defense (eukaryotes) or as a competition strategy for nutrients and space (prokaryotes) [4]. Currently, over 2400 AMPs are reported in The Antimicrobial Peptide Database (URL [5]. The continuous discovery of new AMP groups in diverse organisms has made these natural antibiotics the basic elements of a new generation of potential biomedical treatments against infectious diseases in humans and animals. Moreover, the broad spectrum of biological activities and the low incidence of resistance to these molecules suggest a potential benefit in cancer treatment, which reinforces the importance of their study [6].

AMPs are usually short peptides (12–100 aa residues), which mainly have a positive charge (+2 to +9), although there are also neutral and negatively charged molecules [7]. AMPs are classified into the following four groups according to their structural characteristics: (1) cysteine-rich and β-sheet AMPs (α- and β-defensins); (2) AMPs possessing α-helices (LL-37 cathelicidin, cecropins, and magainins); (3) AMPs with extended structure (rich in glycine, proline, tryptophan, arginine, and/or histidine); (4) peptide “loop,” which have a single disulfide bond (bactenecin) [8]. In recent years, several reviews on the structures, mechanisms of action, and emergence of resistance to AMPs have been published, to which the reader is referred for additional information [911]. Furthermore, recent reviews of the anticancer activities and selectivity and efficacy of AMPs, particularly from animals, have been reported [1215]. The mechanisms by which AMPs kill cancerous cells are poorly understood although evidences indicate that both membranolytic and nonmembranolytic mechanisms are involved. The membranolytic activity of AMPs depends on their own characteristics as well as of the target membrane [13]. Also, the selectivity of some AMPs against cancer cells has been related with the charge of membrane, which has a net negative charge [12]. Anionic molecules (phosphatidylserine, O-glycosylated mucins, sialylated gangliosides, and heparin sulfate) confer a net negative charge to cancer cells, which contrasts with the normal mammalian cell membrane (typically zwitterionic) [14, 15]. On the other hand, the nonmembranolytic activities of AMPs involve the inhibition of processes such as angiogenesis, which is essential for the formation of tumor-associated vasculature [14].

Despite the promising characteristics of anticancer agents such as AMPs, only a few of them have been tested using in vivo models. Cecropin B from Hyalophora cecropia increases the survival time of mice bearing ascitic murine colon adenocarcinoma cells [16]. In the same way, when magainin 2 was tested against murine sarcoma tumors, animals increase its life span (45%) [17]. However, there is little information related to the anticancer effects of plant AMPs. Here, we provide an overview of plant AMP anticancer activities with an emphasis on their mode of action, selectivity, and efficacy. We focus on the anticancer activity reported only for the defensins, thionins, and cyclotides because the cytotoxic effects of these families have been widely described.

2. Plant AMPs

Plants are a major source of diverse molecules with pharmacological potential. Over 300 AMP sequences have been described [5]. Plants produce small cysteine-rich AMPs as a mechanism of natural defense, which may be expressed constitutively or induced in response to a pathogen attack. Plant AMPs are abundantly expressed in the majority species, and small cysteine-rich AMPs may represent up to 3% of the repertoire of plant genes [18]. Plant AMPs are produced in all organs and are more abundant in the outer layer, which is consistent with their role as a constitutive host defense against microbial invaders attacking from the outside [19, 20]. Plant AMPs are released immediately after the infection is initiated. AMPs are expressed by a single gene and therefore require less biomass and energy consumption [19, 20]. The majorities of plant AMPs have a molecular weight between 2 and 10 kDa, are basic, and contain 4, 6, 8, or 12 cysteines that form disulfide bonds conferring structural and thermodynamic stability [21]. Plant AMPs are classified based on the identity of their amino acid sequence and the number and position of cysteines forming disulfide bonds. Twelve families have been described, which are listed in Table 1 [2123].

FamilyDisulfide bondsActivity

Thionins3-4Bacteria, fungi, and cytotoxic
Defensins3-4Bacteria, fungi, and cytotoxic
Cyclotides3Bacteria, virus, insects, and cytotoxic
Knottin-like3Gram (+) bacteria and fungi
Shepherdins0 (linear)Bacteria and fungi
MBP-12Bacteria and fungi
Ib-AMPs2Gram (+) bacteria and fungi
LTP3-4Bacteria and fungi
Snakins6Bacteria and fungi
Hevein-like4Gram (+) bacteria and fungi
2S albumins2Bacteria and fungi

Modified from [2123].

The primary biological activities of plant AMPs are antifungal, antibacterial, and against oomycetes and herbivorous insects [32, 34, 35]. Additionally, plant AMPs also exhibit enzyme inhibitory activities [36] and have roles in heavy metal tolerance [37], abiotic stress [38], and development [39]. In addition, some plant AMPs show cytotoxic activity against mammalian cells and/or anticancer activity against cancer cells from different origins [25, 28, 31, 4056]. Of the 12 plant AMP families, 3 contain members with cytotoxic and anticancer properties, the defensins, thionins, and cyclotides. Here, the cytotoxic properties of these peptides are described and the possibility of their use in cancer treatment is discussed.

3. Thionins

Thionins were the first AMP isolated from plants [57]. These AMPs belong to a rapidly growing family of biologically active peptides in the plant kingdom and are small cysteine-rich peptides (~5 kDa) with toxic and antimicrobial properties [58]. Thionins are divided into at least four different types depending on the net charge, the number of amino acids, and the disulfide bonds present in the mature protein [59]. Type 1 thionins are highly basic and consist of 45 amino acids, eight of which are cysteines, forming four disulfide bonds. Type 2 thionins consist of 46 or 47 amino acid peptides, are slightly less basic than type 1 thionins, and also have four disulfide bonds. Type 3 thionins consist of 45 or 46 amino acid peptides with three or four disulfide bonds and are as basic as type 2 thionins. Finally, type 4 thionins consist of 46 amino acid peptides with three disulfide bonds and are neutral [58].

The primary role for thionins is plant protection against pathogens [57, 59]. However, they also participate in seed maturation, dormancy, or germination [58], as well as the packaging of storage proteins into protein bodies, or in their mobilization during germination [60]. In addition, thionins may play a role in altering the cell wall upon penetration of the epidermis by fungal hyphae or act as a secondary messenger in signal transduction [61].

3.1. Cytotoxic and Anticancer Activity of Thionins

In addition to the activities described, several plant thionins show cytotoxic and anticancer activities (Table 2). The pyrularia thionin from mistletoe (Pyrularia pubera) showed an anticancer activity against cervical cancer cells (HeLa) and mouse melanoma cells (B16) with an IC50 of 50 μg/mL (half maximal inhibitory concentration); however, the pyrularia thionin is cytotoxic because it causes hemolysis [24]. The anticancer effect is attributable to a cellular response that involves the stimulation of Ca2+ influx coupled to depolarization of the plasma membrane, which leads to the activation of an endogenous phospholipase A2 and, as consequence, membrane alteration, and finally the cell death.

NameSpeciesActivity againstCytotoxic activityAnticancer activityReference

Pyrularia Pyrularia pubera B16, HeLa, rat hepatocytes, and lymphocytesYesYes[24]

Viscotoxin B2Viscum coloratum Rat sarcoma cellsNot testedYes[25]

Viscotoxins 1-PS, A1, A2, A3, and BViscum album Human lymphocytesYesNot tested[26]

Viscotoxin C1Coloratum ohwi Rat sarcoma cellsNot testedYes[27]

Ligatoxin BPhoradendron liga U-937-GTB ACHNNot testedYes[28]

Ligatoxin APhoradendron liga Animal cellsYesNot tested[29]

Phoratoxins A and BPhoradendron tomentosum MiceYesNot tested[30]

Phoratoxins C, D, E, and FPhoradendron tomentosum 10 cancer cell linesNot testedYes[31]

Thi2.1Arabidopsis thaliana HeLa, A549, MCF-7, and bovine mammary epithelial cellsYesYes[32]

-PurothioninTricum aestivum p388Not testedYes[33]

Another group of thionins with anticancer and cytotoxic activity are the viscotoxins from Viscum spp. Viscotoxin B2 showed anticancer activity against rat osteoblast-like sarcoma (IC50 1.6 mg/L) [42]. On the other hand, viscotoxins A1, A2, A3, and 1-PS were cytotoxic to human lymphocytes, due the fact that they induce the production of reactive oxygen species (ROS) and cell membrane permeabilization [26]. Furthermore, a mixture of viscotoxins (50 μg/mL) induced apoptosis in human lymphocytes by activating caspase 3 [43]. Conversely, viscotoxins are far less hemolytic than other thionins. Under the same experimental conditions, pyrularia thionin (20 μg/mL) lysed 50% of human erythrocytes, whereas viscotoxin B (100 μg/mL) lysed only 10% [62]. An alignment of the amino acids sequences of both thionins shows that pyrularia has more hydrophobic amino acids compared to the viscotoxin B (Figure 1). These differences could explain the differential hemolytic activity of both thionins because greater hydrophobicity increases the hemolytic activity of AMPs [63].

Another thionin with anticancer activity is the ligatoxin B (Phoradendron league). This AMP (100 μg/mL) inhibited the growth of lymphoma cells (U937GTB) and human adenocarcinoma (ACHN). Ligatoxin B has a DNA binding domain, which may be related to the inhibition of nucleic acid and protein synthesis [28]. Unfortunately, the cytotoxic effects of ligatoxin B have not yet been tested on normal cells.

Several thionins (phoratoxins A–F) have been identified in Phoradendron tomentosum, all of which possess toxic activity. Phoratoxins A and B are toxic to rats at doses of 0.5–1 mg/kg, and their mechanism of action is related to changes in the electrical charge and the mechanical activity of the rat papillary muscle [30]. Furthermore, phoratoxins C–F showed differential anticancer activity against different types of solid tumor cells (NCI-H69, ACHN, and breast carcinoma) and hematological tumors (RPMI 8226-S and U-937 GTB). Phoratoxin C was the most toxic with an IC50 of 0.16 μM, whereas phoratoxin F had an IC50 value of 0.40 μM. Furthermore, phoratoxin C was tested on primary cultures of tumor cells from patients and showed selective activity to breast cancer cells from solid tumor samples. These cells were 18 times more sensitive to phoratoxin C than the hematological tumor cells [31]. These data suggest that these compounds are an alternative for developing a new class of anticancer agents with improved activity against solid tumor malignancies. Despite the marked differences in the activity of phoratoxins, they have a high percentage of identity (~90%) (Figure 1). The small changes in specific amino acids could be the key to the biological activity of these thionins; however, further studies are necessary.

Another thionin with anticancer activity against cancer cell lines is the Thi2.1 thionin from Arabidopsis thaliana, which was expressed in a heterologous system [32]. The conditioned media from cells that express Thi2.1 inhibited the viability of MCF-7 cells (94%), A549 (29%), and HeLa cells (38%); however, Thi2.1 also showed cytotoxicity against bovine mammary epithelial cells (89%) and bovine endothelium (93%). The mechanism of action of Thi2.1 has not yet been determined.

In summary, the cytotoxic activity of thionins is not selective; however, these peptides can be exploited for the design of new anticancer molecules. Further investigations are necessary to determine the clinical potential of this class of compounds.

4. Plant Defensins

Plant defensins are a class of plant AMPs with structural and functional properties that resemble the defense peptides produced by fungi, invertebrates, and vertebrates, called “defensins.” This group of AMPs has great diversity in amino acid sequence, but its members show a clear conservation of some amino acid positions. This variation in the primary sequence is associated with the diversity of biological activities of plant defensins, which include antifungal and antibacterial activities, in addition to proteinase or amylase inhibitory activities [20]. Plant defensins can form three to four disulfide bridges that stabilize their structure [64]. Studies of the three-dimensional structure of plant defensins have shown that these peptides consist of an α-helix and three antiparallel β-sheets, arranged in the configuration βαββ [19]. These AMPs are classified into two types depending on the structure of the precursor protein from which they are derived. Type 1 defensins are the largest group, and the majority of members contain a signal peptide in the prepeptide sequence linked to the mature defensin at the N-terminus. Type 2 defensins include plant defensins for which the precursor has a signal peptide, the active domain of the defensin, and a C-terminal prodomain [20]. Recently, it was demonstrated that the C-terminal prodomain of the NaD1 defensin of Nicotiana alata is sufficient for vacuolar targeting and plays an important role in detoxification of the defensin [65].

Plant defensins inhibit the growth of a wide range of fungi and in a lesser extent are toxic to mammalian cells or plants [66]. The proposed mechanism of action of plant defensins is to either destabilize the cell membrane by coating its outer surface or insert themselves into the membrane to form open pores allowing vital biomolecules to leak out of the cell [34, 64].

4.1. Cytotoxic and Anticancer Activity of Plant Defensins

In addition to the antifungal activities, plant defensins exhibit anticancer and cytotoxic effects (Table 3). The first plant defensin reported with anticancer activity was the defensin sesquin from Vigna sesquipedalis that inhibited the proliferation of MCF-7 and leukemia M1 (2.5 mg/mL) cells [44]. Furthermore, Wong and Ng [41] reported that the defensin limenin (0.1 mg/mL), a defensin from Phaseolus limensis, differentially inhibited the proliferation of leukemia cells, reaching 60% inhibition for M1 and 30% inhibition for L1210 cells; however, its effect against normal cells was not evaluated. Another plant defensin with effects on cancer cell is lunatusin, a defensin purified from the seeds of the Chinese lima bean (Phaseolus lunatus L.), which inhibited the proliferation of MCF-7 cells (IC50 5.71 μM). Unfortunately, lunatusin also possesses cell-free translation-inhibitory activity in the rabbit reticulocyte lysate system [45]. This indicates that this defensin may be cytotoxic to normal tissues and other cell types. However, from all the defensins studied, lunatusin is the only plant defensin with this effect.

NameSpeciesActivity againstCytotoxic activityAnticancer activityReference

Sesquin Vigna sesquipedalis MCF-7 and M1Not testedYes[44]

LimeninPhaseolus limensis L1210 and M1Not testedYes[41]

LunatusinPhaseolus lunatus MCF-7
rabbit reticulocyte

Purple pole defensinPhaseolus vulgaris cv. “Extra-long Purple Pole bean”HepG2, MCF7, HT-29, and SiHaNoYes[46]

CoccininPhaseolus coccineus cv. “Major”HL60 and L1210NoYes[47]

PhaseococcinPhaseolus coccineus L1210 and HL60NoYes[48]

-ThioninCapsicum chinense HeLaNoYes[49]

NaD1Nicotiana alata U937Not testedYes[67]

Mitogenic defensinPhaseolus vulgaris MCF-7, murine splenocytesYesYes[68]

VulgarininPhaseolus vulgaris MCF-7, L1210, and M1Not testedYes[69]

Cloud bean defensinPhaseolus vulgaris cv. cloud beanL1210 and MBL2Not testedYes[70]

NepalesePhaseolus angularis L1210, MBL2Not testedYes[71]

GymninGymnocladus chinensis BaillM1, HepG2, and L1210Not testedYes[72]

Further studies identified other plant defensins that inhibit the proliferation of cancer cells, including breast and colon cancer, without cytotoxic effects on normal cells. A defensin from the purple pole bean (Phaseolus vulgaris cv. “Extra-long Purple Pole bean”) inhibited the proliferation of the cancer cell lines HepG2, MCF-7, HT-29, and Sila (IC50 4–8 μM) but did not affect human embryonic liver cells or human erythrocytes under the same conditions [46]. By contrast, coccinin from small scarlet runner beans (Phaseolus coccineus cv. “Major”), a peptide of 7 kDa and an N-terminal sequence resembling those of defensins, inhibited the proliferation of HL60 and L1210 cells (IC50 30–40 μM); however, it did not affect the proliferation of mouse splenocytes [47]. Similarly, phaseococcin from P. coccineus cv. “Minor” inhibited the proliferation of HL60 and L1210 cells (IC50 30–40 μM). This defensin did not affect the proliferation of mouse splenocytes or protein synthesis in a cell-free rabbit reticulocyte lysate system [48]. The lack of adverse effects of both of these defensins on the proliferation of isolated mouse splenocytes indicates that these molecules are selective. Finally, the conditioned media from bovine endothelial cells that express the cDNA of the defensin γ-thionin from Capsicum chinense inhibited 100% of the viability of HeLa cells but did not affect immortalized bovine endothelial cells [49]. Data from our laboratory indicate that this chemically synthetized defensin has a similar effect on both cells (data not published).

In general, the anticancer activity mechanism of plant defensins is poorly understood. However, Poon et al. [67] described the mechanism of the NaD1 defensin on the monocytic lymphoma cells U937. Interestingly, this effect was produced by a novel mechanism of cell lysis in which NaD1 acts via direct binding to the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2).

Thus, the anticancer activities of plant defensins suggest that these AMPs may be an alternative therapy for cancer treatment. The isolation and characterization of these peptides has increased, which allows for the identification of sequences that exhibit desirable characteristics against cancer cells.

5. Cyclotides

Cyclotides are macrocyclic peptides (~30 amino acids) with diverse biological activities, isolated from the Rubiaceae and Violaceae plant families. These molecules constitute a family of plant AMPs, members of which contain six conserved cysteines that stabilize the structure by the formation of disulfide bonds [74]. Cyclotides have a cystine knot with an embedded ring in the structure formed by two disulfide bonds and connecting backbone segments threaded by a third disulfide bond. These combined features of the cyclic cystine knot produce a unique protein fold that is topologically complex and has exceptional chemical and biological stability with pharmaceutical and medicinal significance for drug design [75].

Cyclotides are biosynthesized ribosomally as a precursor protein that encodes one or more cyclotide domains. The arrangement of a typical cyclotide precursor protein is an endoplasmic reticulum signal sequence, a prodomain, a mature cyclotide domain, and a C-terminal region [76]. Although the excision and cyclization processes that yield cyclic mature peptides from these precursors are not fully understood, it has been suggested that asparaginyl endoproteinase enzyme activity plays an important role in this process [77]. This hypothesis is consistent with the presence of a conserved Asn (or Asp) residue at the C-terminus of the cyclotide domain within the precursor proteins (Figure 2(a)). It is also supported by studies of the expression of mutated cyclotides in transgenic plants, in which substitution of the conserved Asn by Ala abolished the production of cyclic peptides in planta [78].

The main role attributable to cyclotides is host defense, and there are molecules that are expressed in large quantities in the plant (up to 1 g/kg of leaf material) [75]. Furthermore, cyclotides display a wide range of biological and pharmacological activities, including anti-HIV, anthelmintic, insecticidal, antimicrobial, and cytotoxic effects [79]. Therefore, there is increasing interest in exploring the plant kingdom to identify new cyclotides.

5.1. Cytotoxic and Anticancer Activity of Cyclotides

One of the first activities reported for cyclotides was hemolytic activity, which only occurs in the cyclic condition. Cyclotides lose their hemolytic activity when they are linearized [80], demonstrating that the cyclic backbone is important for this activity, which also appears to be important for the other activities of cyclotides. A directed mutational analysis of cyclotide kalata B1, in which all 23 noncysteine residues were replaced with alanine, shows that both the insecticidal and hemolytic activities are dependent on a well-defined cluster of hydrophilic residues on one face of the cyclotide. Interestingly, these molecules retain the characteristic stability of the framework [73]. In addition, it has been suggested that the hemolytic activity of the cyclotides depends on the amino acid sequence. The cyclotides cycloviolacins O2 and O13 from Viola odorata have different hemolytic activities. Both molecules differ only in one residue (Figure 2(b)). Cycloviolacin O2 has a serine residue, whereas cycloviolacin O13 has an alanine in the same position. The loss of the hydroxyl group changes the hemolytic activity by more than 3-fold [50].

In general, cyclotides also show anticancer activity against human cancer cells (Table 4); however, two cyclotides from Viola philippica (Viphi D and Viphi E) did not show activity against the human gastric cancer BGC-823 cell line [51]. These peptides have similar sequences to the cyclotides Viphi F and Viphi G (Figure 2(c)), indicating that even minimal sequence changes can significantly influence the bioactivity. It has been suggested that the potency and selectivity of cyclotides is dependent on their primary structure. For example, a single glutamic acid plays a key role in the anticancer activity of cycloviolacin O2, and when this residue is methylated, a 48-fold decrease in potency is observed [52].

NameSpeciesActivity againstCytotoxic activityAnticancer activityReference

Cycloviolacin O2Viola odorata U-937, HeLaYesYes[54]

Viphi A, Viphi F, and Viphi GViola philippica MM96L, HeLa, BGC-823, and HFF-1YesYes[51]

MCoTI-IMomordica cochinchinensis LNCaP and HCT116Not testedYes[81]

HB7Hedyotis biflora Capan2 and PANC1Not testedYes[82]

Vaby A and Vaby DViola abyssinica U-937Not testedYes[83]

Cliotides T1–T4 Clitoria ternatea HeLa and human erythrocytesYesYes[84]

Psyle A, Psyle C, and Psyle EPsychotria leptothyrsa U-937Not testedYes[85]

Vibi G and Vibi HViola biflora U-937Not testedYes[86]

Varv A and Varv FViola arvensis 10 cancer cell linesNot testedYes[87]

Viba 15, Viba 17, and Mram 8Viola philippica HFF1, MM96L, HeLa, BGC-823, and HFF-1YesYes[51]

CT-2, CT-4, CT-7, CT-10, CT-12, and CT-19Clitoria ternatea A549Not testedYes[88]

Kalata B1 and kalata B2Oldenlandia  affinis U-937 GTB

Cycloviolacin O2 from Viola odorata is particular promising because of its selective toxicity to cancer cell lines relative to normal cells, which indicates the possibility of its use as an anticancer agent [53]. Analysis of the proposed mechanism of action of this cyclotide shows that the disruption of cell membranes plays a crucial role in the cytotoxicity of cycloviolacin O2 because the damage to cancer cells (human lymphoma) can be morphologically distinguished within a few minutes, indicating necrosis [54]. However, this activity was not detected when this cyclotide was tested in a mouse tumor model. The reasons of this discrepancy are not fully understood, although high clearance rates or poor distribution to the site of action may be involved. Cycloviolacin O2 was also lethal to mice (2 mg/kg), but no signs of discomfort to the animals were observed at 1.5 mg/kg [55]. Recently the cyclotide MCoTI-I was engineering and the resulting cyclotide MCo-PMI showed activity in vivo in a murine xenograft model with prostate cancer cell; treatment (40 mg/kg) significantly suppressed tumor growth [81]. In the same way, HB7 cyclotide from Hedyotis biflora in an in vivo xenograft model significantly inhibited the tumor weight and size compared to control [82]. These results suggest that cyclotides may have a good anticancer bioactivity.

With respect to the action mechanism of cyclotides, a study showed that cycloviolacin O2 and kalatas B1–B9 target membranes through binding to phospholipids containing phosphatidylethanolamine headgroups [90]. Therefore, the biological potency of these cyclotides may be correlated with their ability to target and disrupt cell membranes. The knowledge of their membrane specificity could be useful to design novel drugs based on the cyclotide framework, allowing the targeting of specific peptide drugs to different cell types.

6. Small Cationic Peptides Isolated from Plants with Anticancer Activity

In addition to plant AMPs, other small linear and cyclic peptides (2–10 aa) with anticancer activity have been reported in plants. For example, the linear peptide Cn-AMP1, isolated and purified from coconut water (Cocos nucifera), was tested against Caco-2, RAW264.7, MCF-7, HCT-116 cells, and human erythrocytes and showed a reduction of cell viability in cancer cells without causing hemolysis [91]. Other examples are the peptides Cr-ACP, isolated from Cycas revoluta, and the acetylated-modified Cr-AcACP1, both repressors of cell proliferation of human epidermoid cancer (Hep2) and colon carcinoma. These peptides induce cell cycle arrest at the G0-G1 phase of Hep2 cells [92]. Moreover, four small cyclic peptides, dianthins C–F, have anticancer activity against Hep G2, Hep 3B, MCF-7, A-549, and MDA-MB-231 cancer cell lines (IC50 20 μg/mL) [93]. Furthermore, the cyclic heptapeptide cherimolacyclopeptide C, obtained from a methanol extract of the seeds of Annona cherimola, exhibited significant in vitro cytotoxicity against KB cells (IC50 0.072 μM) [94]. Other examples of small cyclic peptides are RA-XVII and RA-XVIII from the roots of Rubia cordifolia L., which have cytotoxicity against P-388 cells at 0.0030 μg/mL and 0.012 μg/mL, respectively; however, it was not determined whether these peptides are effective against normal cells [95]. Recently, an antiproliferative cyclic octapeptide (cyclosaplin) was purified from Santalum album L. The anticancer activity from this peptide was tested against human breast cancer (MDA-MB-231) cells and exhibited significant growth inhibition in a dose and time dependent manner (IC50 2.06 μg/mL). Additionally, cytotoxicity on normal fibroblast cell line at concentrations up to 1000 μg/mL was not detected [56].

7. Conclusion and Future Perspectives

The identification and development of plant AMPs with anticancer properties will provide good opportunities for cancer treatment. AMPs with anticancer activities, including plant-derived peptides, show many therapeutic challenges that must be considered before they can be developed commercially. Strategies to solve their poor stability and susceptibility to proteolytic digestion, such as amino acid substitution, structural fusion of functional peptides, and conjugation with chemotherapeutic drugs, must be evaluated. Despite these limitations, AMPs are an important source of molecules useful for the design of new drugs. In this sense, cationic peptides from plants have great potential as anticancer agents, particularly because of their selectivity towards cancer cells, as has been demonstrated to coccinin and phaseococcin. The number of plant AMPs with anticancer activity is increasing and is expected to rise in the next years, particularly when the remaining plant AMP families are assessed. A crucial step in the studies of plant AMPs as anticancer agents is the identification of their mechanisms of action to discover new targets. Furthermore, the development of novel synthetic analogs of these natural molecules could enhance their activities, facilitating the development of new drugs. With the rapid development in proteomics, bioinformatics, peptide libraries, and modification strategies, these plant AMPs emerge as novel promising anticancer drugs in future clinical applications.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


A grant from CIC-UMSNH to Joel E. López-Meza (CIC14.5) supported this publication. J. J. Guzmán-Rodríguez was supported by a scholarship from CONACyT.


  1. J. Ferlay, I. Soerjomataram, M. Ervik et al., GLOBOCAN 2012: Cancer Incidence And Mortality Worldwide, vol. 1.0 of IARC Cancer Base no. 11, International Agency for Research on Cancer, Lyon, France, 2013,
  2. H. Zahreddine and K. L. B. Borden, “Mechanisms and insights into drug resistance in cancer,” Frontiers in Pharmacology, vol. 4, article 28, 2013. View at: Publisher Site | Google Scholar
  3. S. Al-Benna, Y. Shai, F. Jacobsen, and L. Steinstraesser, “Oncolytic activities of host defense peptides,” International Journal of Molecular Sciences, vol. 12, no. 11, pp. 8027–8051, 2011. View at: Publisher Site | Google Scholar
  4. E. Guaní-Guerra, T. Santos-Mendoza, S. O. Lugo-Reyes, and L. M. Terán, “Antimicrobial peptides: general overview and clinical implications in human health and disease,” Clinical Immunology, vol. 135, no. 1, pp. 1–11, 2010. View at: Publisher Site | Google Scholar
  5. G. Wang, X. Li, and Z. Wang, “APD2: the updated antimicrobial peptide database and its application in peptide design,” Nucleic Acids Research, vol. 37, no. 1, pp. D933–D937, 2009. View at: Publisher Site | Google Scholar
  6. M.-D. Seo, H.-S. Won, J.-H. Kim, T. Mishig-Ochir, and B.-J. Lee, “Antimicrobial peptides for therapeutic applications: a review,” Molecules, vol. 17, no. 10, pp. 12276–12286, 2012. View at: Publisher Site | Google Scholar
  7. M. Zasloff, “Antimicrobial peptides of multicellular organisms,” Nature, vol. 415, no. 6870, pp. 389–395, 2002. View at: Publisher Site | Google Scholar
  8. R. E. W. Hancock and H.-G. Sahl, “Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies,” Nature Biotechnology, vol. 24, no. 12, pp. 1551–1557, 2006. View at: Publisher Site | Google Scholar
  9. M. Pushpanathan, P. Gunasekaran, and J. Rajendhran, “Antimicrobial peptides: versatile biological properties,” International Journal of Peptides, vol. 2013, Article ID 675391, 15 pages, 2013. View at: Publisher Site | Google Scholar
  10. F. Guilhelmelli, N. Vilela, P. Albuquerque, L. D. S. Derengowski, I. Silva-Pereira, and C. M. Kyaw, “Antibiotic development challenges: the various mechanisms of action of antimicrobial peptides and of bacterial resistance,” Frontiers in Microbiology, vol. 4, article 353, pp. 1–12, 2013. View at: Publisher Site | Google Scholar
  11. J. L. Anaya-López, J. E. López-Meza, and A. Ochoa-Zarzosa, “Bacterial resistance to cationic antimicrobial peptides,” Critical Reviews in Microbiology, vol. 39, no. 2, pp. 180–195, 2013. View at: Publisher Site | Google Scholar
  12. D. Gaspar, A. S. Veiga, and M. A. R. B. Castanho, “From antimicrobial to anticancer peptides. A review,” Frontiers in Microbiology, vol. 4, article 294, 2013. View at: Publisher Site | Google Scholar
  13. K. C. Mulder, L. A. Lima, V. J. Miranda, S. C. Dias, and O. L. Franco, “Current scenario of peptide-based drugs: the key roles of cationic antitumor and antiviral peptides,” Frontiers in Microbiology, vol. 4, article 321, 23 pages, 2013. View at: Publisher Site | Google Scholar
  14. F. Schweizer, “Cationic amphiphilic peptides with cancer-selective toxicity,” European Journal of Pharmacology, vol. 625, no. 1–3, pp. 190–194, 2009. View at: Publisher Site | Google Scholar
  15. D. W. Hoskin and A. Ramamoorthy, “Studies on anticancer activities of antimicrobial peptides,” Biochimica et Biophysica Acta—Biomembranes, vol. 1778, no. 2, pp. 357–375, 2008. View at: Publisher Site | Google Scholar
  16. A. J. Moore, D. A. Devine, and M. C. Bibby, “Preliminary experimental anticancer activity of cecropins,” Peptide Research, vol. 7, no. 5, pp. 265–269, 1994. View at: Google Scholar
  17. M. A. Baker, W. L. Maloy, M. Zasloff, and L. S. Jacob, “Anticancer efficacy of Magainin2 and analogue peptides,” Cancer Research, vol. 53, no. 13, pp. 3052–3057, 1993. View at: Google Scholar
  18. K. A. Silverstein, W. A. Moskal Jr., H. C. Wu et al., “Small cysteine-rich peptides resembling antimicrobial peptides have been under-predicted in plants,” Plant Journal, vol. 51, no. 2, pp. 262–280, 2007. View at: Publisher Site | Google Scholar
  19. B. P. H. J. Thomma, B. P. A. Cammue, and K. Thevissen, “Plant defensins,” Planta, vol. 216, no. 2, pp. 193–202, 2002. View at: Publisher Site | Google Scholar
  20. F. T. Lay and M. A. Anderson, “Defensins—components of the innate immune system in plants,” Current Protein & Peptide Science, vol. 6, no. 1, pp. 85–101, 2005. View at: Publisher Site | Google Scholar
  21. F. García-Olmedo, P. Rodríguez-Palenzuela, A. Molina et al., “Antibiotic activities of peptides, hydrogen peroxide and peroxynitrite in plant defence,” FEBS Letters, vol. 498, no. 2-3, pp. 219–222, 2001. View at: Publisher Site | Google Scholar
  22. J. P. Marcus, K. C. Goulter, J. L. Green, S. J. Harrison, and J. M. Manners, “Purification, characterisation and cDNA cloning of an antimicrobial peptide from Macadamia integrifolia,” European Journal of Biochemistry, vol. 244, no. 3, pp. 743–749, 1997. View at: Publisher Site | Google Scholar
  23. E. de Souza Cândido, M. F. S. Pinto, P. B. Pelegrini et al., “Plant storage proteins with antimicrobial activity: novel insights into plant defense mechanisms,” The FASEB Journal, vol. 25, no. 10, pp. 3290–3305, 2011. View at: Publisher Site | Google Scholar
  24. J. Evans, Y. D. Wang, K. P. Shaw, and L. P. Vernon, “Cellular responses to Pyrularia thionin are mediated by Ca2+ influx and phospholipase A2 activation and are inhibited by thionin tyrosine iodination,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 15, pp. 5849–5853, 1989. View at: Publisher Site | Google Scholar
  25. J. L. Kong, X. B. Du, C. X. Fan et al., “Purification and primary structure determination of a novel polypeptide isolated from mistletoe Viscum coloratum,” Chinese Chemical Letters, vol. 15, no. 11, pp. 1311–1314, 2004. View at: Google Scholar
  26. A. Büssing, G. M. Stein, M. Wagner et al., “Accidental cell death and generation of reactive oxygen intermediates in human lymphocytes induced by thionins from Viscum album L,” European Journal of Biochemistry, vol. 262, no. 1, pp. 79–87, 1999. View at: Publisher Site | Google Scholar
  27. S. Romagnoli, F. Fogolari, M. Catalano et al., “NMR solution structure of viscotoxin C1 from viscum album species Coloratum ohwi: Toward a structure-function analysis of viscotoxins,” Biochemistry, vol. 42, no. 43, pp. 12503–12510, 2003. View at: Publisher Site | Google Scholar
  28. S.-S. Li, J. Gullbo, P. Lindholm et al., “Ligatoxin B, a new cytotoxic protein with a novel helix-turn-helix DNA-binding domain from the mistletoe Phoradendron liga,” Biochemical Journal, vol. 366, no. part 2, pp. 405–413, 2002. View at: Publisher Site | Google Scholar
  29. F. Thunberg and G. Samuelsson, “Isolation and properties of ligatoxin A, a toxic protein from the mistletoe Phoradendron liga,” Acta Pharmaceutica Suecica, vol. 19, no. 4, pp. 285–292, 1982. View at: Google Scholar
  30. M. P. Sauviat, J. Berton, and C. Pater, “Effect of phoratoxin B on electrical and mechanical activities of rat papillary muscle,” Acta Pharmacologica Sinica, vol. 6, no. 2, pp. 91–93, 1985. View at: Google Scholar
  31. S. Johansson, J. Gullbo, P. Lindholm et al., “Small, novel proteins from the mistletoe Phoradendron tomentosum exhibit highly selective cytotoxicity to human breast cancer cells,” Cellular and Molecular Life Sciences, vol. 60, no. 1, pp. 165–175, 2003. View at: Publisher Site | Google Scholar
  32. H. Loeza-Ángeles, E. Sagrero-Cisneros, L. Lara-Zárate, E. Villagómez-Gómez, J. E. López-Meza, and A. Ochoa-Zarzosa, “Thionin Thi2.1 from Arabidopsis thaliana expressed in endothelial cells shows antibacterial, antifungal and cytotoxic activity,” Biotechnology Letters, vol. 30, no. 10, pp. 1713–1719, 2008. View at: Publisher Site | Google Scholar
  33. P. Hughes, E. Dennis, M. Whitecross, D. Llewellyn, and P. Gage, “The cytotoxic plant protein, β-purothionin, forms ion channels in lipid membranes,” The Journal of Biological Chemistry, vol. 275, no. 2, pp. 823–827, 2000. View at: Publisher Site | Google Scholar
  34. P. Barbosa Pelegrini, R. P. del Sarto, O. N. Silva, O. L. Franco, and M. F. Grossi-De-Sa, “Antibacterial peptides from plants: what they are and how they probably work,” Biochemistry Research International, vol. 2011, Article ID 250349, 9 pages, 2011. View at: Publisher Site | Google Scholar
  35. H. U. Stotz, F. Waller, and K. Wang, “Innate immunity in plants: the role of antimicrobial peptides,” in Antimicrobial Peptides and Innate Immunity, P. S. Hiemstra and S. A. J. Zaat, Eds., pp. 29–51, Springer Science & Business Media, Broken Arrow, Okla, USA, 2013. View at: Google Scholar
  36. P. H. K. Ngai and T. B. Ng, “A napin-like polypeptide from dwarf Chinese white cabbage seeds with translation-inhibitory, trypsin-inhibitory, and antibacterial activities,” Peptides, vol. 25, no. 2, pp. 171–176, 2004. View at: Publisher Site | Google Scholar
  37. M. Mirouze, J. Sels, O. Richard et al., “A putative novel role for plant defensins: a defensin from the zinc hyper-accumulating plant, Arabidopsis halleri, confers zinc tolerance,” The Plant Journal, vol. 47, no. 3, pp. 329–342, 2006. View at: Publisher Site | Google Scholar
  38. M. Koike, T. Okamoto, S. Tsuda, and R. Imai, “A novel plant defensin-like gene of winter wheat is specifically induced during cold acclimation,” Biochemical and Biophysical Research Communications, vol. 298, no. 1, pp. 46–53, 2002. View at: Publisher Site | Google Scholar
  39. A. Allen, A. K. Snyder, M. Preuss, E. E. Nielsen, D. M. Shah, and T. J. Smith, “Plant defensins and virally encoded fungal toxin KP4 inhibit plant root growth,” Planta, vol. 227, no. 2, pp. 331–339, 2008. View at: Publisher Site | Google Scholar
  40. L. Carrasco, D. Vázquez, C. Hernández-Lucas, P. Carbonero, and F. García-Olmedo, “Thionins: plant peptides that modify membrane permeability in cultured mammalian cells,” European Journal of Biochemistry, vol. 116, no. 1, pp. 185–189, 1981. View at: Publisher Site | Google Scholar
  41. J. H. Wong and T. B. Ng, “Limenin, a defensin-like peptide with multiple exploitable activities from shelf beans,” Journal of Peptide Science, vol. 12, no. 5, pp. 341–346, 2006. View at: Publisher Site | Google Scholar
  42. J. L. Kong, X. B. Du, C. X. Fan, J. F. Xu, and X. J. Zheng, “Determination of primary structure of a novel peptide from mistletoe and its antitumor activity,” Acta Pharmaceutica Sinica, vol. 39, no. 10, Article ID 0513-4870(2004)10-0813-05, pp. 813–817, 2004. View at: Google Scholar
  43. A. Büssing, W. Vervecken, M. Wagner, B. Wagner, U. Pfüller, and M. Schietzel, “Expression of mitochondrial Apo2.7 molecules and caspase-3 activation in human lymphocytes treated with the ribosome-inhibiting mistletoe lectins and the cell membrane permeabilizing viscotoxins,” Cytometry, vol. 37, no. 2, pp. 133–139, 1999. View at: Google Scholar
  44. J. H. Wong and T. B. Ng, “Sesquin, a potent defensin-like antimicrobial peptide from ground beans with inhibitory activities toward tumor cells and HIV-1 reverse transcriptase,” Peptides, vol. 26, no. 7, pp. 1120–1126, 2005. View at: Publisher Site | Google Scholar
  45. J. H. Wong and T. B. Ng, “Lunatusin, a trypsin-stable antimicrobial peptide from lima beans (Phaseolus lunatus L.),” Peptides, vol. 26, no. 11, pp. 2086–2092, 2005. View at: Publisher Site | Google Scholar
  46. P. Lin, J. H. Wong, and T. B. Ng, “A defensin with highly potent antipathogenic activities from the seeds of purple pole bean,” Bioscience Reports, vol. 30, no. 2, pp. 101–109, 2010. View at: Google Scholar
  47. P. H. K. Ngai and T. B. Ng, “Coccinin, an antifungal peptide with antiproliferative and HIV-1 reverse transcriptase inhibitory activities from large scarlet runner beans,” Peptides, vol. 25, no. 12, pp. 2063–2068, 2004. View at: Publisher Site | Google Scholar
  48. P. H. K. Ngai and T. B. Ng, “Phaseococcin, an antifungal protein with antiproliferative and anti-HIV-1 reverse transcriptase activities from small scarlet runner beans,” Biochemistry and Cell Biology, vol. 83, no. 2, pp. 212–220, 2005. View at: Publisher Site | Google Scholar
  49. J. L. Anaya-López, J. E. López-Meza, V. M. Baizabal-Aguirre, H. Cano-Camacho, and A. Ochoa-Zarzosa, “Fungicidal and cytotoxic activity of a Capsicum chinense defensin expressed by endothelial cells,” Biotechnology Letters, vol. 28, no. 14, pp. 1101–1108, 2006. View at: Publisher Site | Google Scholar
  50. D. C. Ireland, M. L. Colgrave, and D. J. Craik, “A novel suite of cyclotides from Viola odorata: sequence variation and the implications for structure, function and stability,” The Biochemical Journal, vol. 400, no. 1, pp. 1–12, 2006. View at: Publisher Site | Google Scholar
  51. W. He, L. Y. Chan, G. Zeng, N. L. Daly, D. J. Craik, and N. Tan, “Isolation and characterization of cytotoxic cyclotides from Viola philippica,” Peptides, vol. 32, no. 8, pp. 1719–1723, 2011. View at: Publisher Site | Google Scholar
  52. A. Herrmann, E. Svangård, P. Claeson, J. Gullbo, L. Bohlin, and U. Göransson, “Key role of glutamic acid for the cytotoxic activity of the cyclotide cycloviolacin O2,” Cellular and Molecular Life Sciences, vol. 63, no. 2, pp. 235–245, 2006. View at: Publisher Site | Google Scholar
  53. S. L. Gerlach, R. Rathinakumar, G. Chakravarty et al., “Anticancer and chemosensitizing abilities of cycloviolacin O2 from Viola odorata and psyle cyclotides from Psychotria leptothyrsa,” Biopolymers, vol. 94, no. 5, pp. 617–625, 2010. View at: Publisher Site | Google Scholar
  54. E. Svangård, R. Burman, S. Gunasekera, H. Lövborg, J. Gullbo, and U. Göransson, “Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes,” Journal of Natural Products, vol. 70, no. 4, pp. 643–647, 2007. View at: Publisher Site | Google Scholar
  55. R. Burman, E. Svedlund, J. Felth et al., “Evaluation of toxicity and antitumor activity of cycloviolacin O2 in mice,” Biopolymers, vol. 94, no. 5, pp. 626–634, 2010. View at: Publisher Site | Google Scholar
  56. A. Mishra, S. S. Gauri, S. K. Mukhopadhyay et al., “Identification and structural characterization of a new pro-apoptotic cyclic octapeptide cyclosaplin from somatic seedlings of Santalum album L,” Peptides, vol. 54, pp. 148–158, 2014. View at: Publisher Site | Google Scholar
  57. R. Fernandez de Caleya, B. Gonzalez-Pascual, F. García-Olmedo, and P. Carbonero, “Susceptibility of phytopathogenic bacteria to wheat purothionins in vitro,” Applied Microbiology, vol. 23, no. 5, pp. 998–1000, 1972. View at: Google Scholar
  58. D. E. A. Florack and W. J. Stiekema, “Thionins: properties, possible biological roles and mechanisms of action,” Plant Molecular Biology, vol. 26, no. 1, pp. 25–37, 1994. View at: Publisher Site | Google Scholar
  59. H. Bohlmann and K. Apel, “Thionins,” Annual Review of Plant Physiology and Plant Molecular Biology, vol. 42, no. 1, pp. 227–240, 1991. View at: Publisher Site | Google Scholar
  60. M. J. Carmona, C. Hernández-Lucas, C. San Martin, P. González, and F. García-Olmedo, “Subcellular localization of type I thionins in the endosperms of wheat and barley,” Protoplasma, vol. 173, no. 1-2, pp. 1–7, 1993. View at: Publisher Site | Google Scholar
  61. B. Stec, “Plant thionins—the structural perspective,” Cellular and Molecular Life Sciences, vol. 63, no. 12, pp. 1370–1385, 2006. View at: Publisher Site | Google Scholar
  62. A. Coulon, E. Berkane, A.-M. Sautereau, K. Urech, P. Rougé, and A. López, “Modes of membrane interaction of a natural cysteine-rich peptide: viscotoxin A3,” Biochimica et Biophysica Acta, vol. 1559, no. 2, pp. 145–159, 2002. View at: Publisher Site | Google Scholar
  63. Y. Chen, M. T. Guarnieri, A. I. Vasil, M. L. Vasil, C. T. Mant, and R. S. Hodges, “Role of peptide hydrophobicity in the mechanism of action of α-helical antimicrobial peptides,” Antimicrobial Agents and Chemotherapy, vol. 51, no. 4, pp. 1398–1406, 2007. View at: Publisher Site | Google Scholar
  64. A. F. Lacerda, É. A. R. Vasconcelos, P. B. Pelegrini, and M. F. Grossi de Sa, “Antifungal defensins and their role in plant defense,” Frontiers in Microbiology, vol. 5, no. 116, pp. 1–10, 2014. View at: Publisher Site | Google Scholar
  65. F. T. Lay, S. Poon, J. A. McKenna et al., “The C-terminal propeptide of a plant defensin confers cytoprotective and subcellular targeting functions,” BMC Plant Biology, vol. 14, no. 1, article 41, 2014. View at: Publisher Site | Google Scholar
  66. K. Vriens, B. P. A. Cammue, and K. Thevissen, “Antifungal plant defensins: mechanisms of action and production,” Molecules, vol. 19, no. 8, pp. 12280–12303, 2014. View at: Google Scholar
  67. I. K. H. Poon, A. A. Baxter, F. T. Lay et al., “Phosphoinositide-mediated oligomerization of a defensin induces cell lysis,” eLife, vol. 3, Article ID e01808, 27 pages, 2014. View at: Publisher Site | Google Scholar
  68. J. H. Wong, X. Q. Zhang, H. X. Wang, and T. B. Ng, “A mitogenic defensin from white cloud beans (Phaseolus vulgaris),” Peptides, vol. 27, no. 9, pp. 2075–2081, 2006. View at: Publisher Site | Google Scholar
  69. H. W. Jack and B. N. Tzi, “Vulgarinin, a broad-spectrum antifungal peptide from haricot beans (Phaseolus vulgaris),” International Journal of Biochemistry and Cell Biology, vol. 37, no. 8, pp. 1626–1632, 2005. View at: Publisher Site | Google Scholar
  70. X. Wu, J. Sun, G. Zhang, H. Wang, and T. B. Ng, “An antifungal defensin from Phaseolus vulgaris cv. ‘Cloud Bean’,” Phytomedicine, vol. 18, no. 2-3, pp. 104–109, 2011. View at: Publisher Site | Google Scholar
  71. D. Z. Ma, H. X. Wang, and T. B. Ng, “A peptide with potent antifungal and antiproliferative activities from Nepalese large red beans,” Peptides, vol. 30, no. 12, pp. 2089–2094, 2009. View at: Publisher Site | Google Scholar
  72. J. H. Wong and T. B. Ng, “Gymnin, a potent defensin-like antifungal peptide from the Yunnan bean (Gymnocladus chinensis Baill),” Peptides, vol. 24, no. 7, pp. 963–968, 2003. View at: Publisher Site | Google Scholar
  73. S. M. Simonsen, L. Sando, K. J. Rosengren et al., “Alanine scanning mutagenesis of the prototypic cyclotide reveals a cluster of residues essential for bioactivity,” The Journal of Biological Chemistry, vol. 283, no. 15, pp. 9805–9813, 2008. View at: Publisher Site | Google Scholar
  74. C. K. Wang, H. Shu-Hong, J. L. Martin et al., “Combined x-ray and NMR analysis of the stability of the cyclotide cystine knot fold that underpins its insecticidal activity and potential use as a drug scaffold,” The Journal of Biological Chemistry, vol. 284, no. 16, pp. 10672–10683, 2009. View at: Publisher Site | Google Scholar
  75. D. J. Craik, N. L. Daly, T. Bond, and C. Waine, “Plant cyclotides: a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif,” Journal of Molecular Biology, vol. 294, no. 5, pp. 1327–1336, 1999. View at: Publisher Site | Google Scholar
  76. J. L. Dutton, R. F. Renda, C. Waine et al., “Conserved structural and sequence elements implicated in the processing of gene-encoded circular proteine,” The Journal of Biological Chemistry, vol. 279, no. 45, pp. 46858–46867, 2004. View at: Publisher Site | Google Scholar
  77. I. Saska, A. D. Gillon, N. Hatsugai et al., “An asparaginyl endopeptidase mediates in vivo protein backbone cyclization,” The Journal of Biological Chemistry, vol. 282, no. 40, pp. 29721–29728, 2007. View at: Publisher Site | Google Scholar
  78. A. D. Gillon, I. Saska, C. V. Jennings, R. F. Guarino, D. J. Craik, and M. A. Anderson, “Biosynthesis of circular proteins in plants,” Plant Journal, vol. 53, no. 3, pp. 505–515, 2008. View at: Publisher Site | Google Scholar
  79. D. J. Craik, “Host-defense activities of cyclotides,” Toxins, vol. 4, no. 2, pp. 139–156, 2012. View at: Publisher Site | Google Scholar
  80. D. G. Barry, N. L. Daly, R. J. Clark, L. Sando, and D. J. Craik, “Linearization of a naturally occurring circular protein maintains structure but eliminates hemolytic activity,” Biochemistry, vol. 42, no. 22, pp. 6688–6695, 2003. View at: Publisher Site | Google Scholar
  81. Y. Ji, S. Majumder, M. Millard et al., “In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide,” Journal of the American Chemical Society, vol. 135, no. 31, pp. 11623–11633, 2013. View at: Publisher Site | Google Scholar
  82. X. Ding, D. Bai, and J. Qian, “Novel cyclotides from Hedyotis biflora inhibit proliferation and migration of pancreatic cancer cell in vitro and in vivo,” Medicinal Chemistry Research, vol. 23, no. 3, pp. 1406–1413, 2014. View at: Publisher Site | Google Scholar
  83. M. Y. Yeshak, R. Burman, K. Asres, and U. Göransson, “Cyclotides from an extreme habitat: characterization of cyclic peptides from viola abyssinica of the ethiopian highlands,” Journal of Natural Products, vol. 74, no. 4, pp. 727–731, 2011. View at: Publisher Site | Google Scholar
  84. G. K. T. Nguyen, S. Zhang, N. T. K. Nguyen et al., “Discovery and characterization of novel cyclotides originated from chimeric precursors consisting of albumin-1 chain a and cyclotide domains in the fabaceae family,” The Journal of Biological Chemistry, vol. 286, no. 27, pp. 24275–24287, 2011. View at: Publisher Site | Google Scholar
  85. S. L. Gerlach, R. Burman, L. Bohlin, D. Mondal, and U. Göransson, “Isolation, characterization, and bioactivity of cyclotides from the micronesian plant Psychotria leptothyrsa,” Journal of Natural Products, vol. 73, no. 7, pp. 1207–1213, 2010. View at: Publisher Site | Google Scholar
  86. A. Herrmann, R. Burman, J. S. Mylne et al., “The alpine violet, Viola biflora, is a rich source of cyclotides with potent cytotoxicity,” Phytochemistry, vol. 69, no. 4, pp. 939–952, 2008. View at: Publisher Site | Google Scholar
  87. P. Lindholm, U. Göransson, S. Johansson et al., “Cyclotides: a novel type of cytotoxic agents,” Molecular Cancer Therapeutics, vol. 1, no. 6, pp. 365–369, 2002. View at: Google Scholar
  88. S. Zhang, K. Z. Xiao, J. Jin, Y. Zhang, and W. Zhou, “Chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells,” Oncology Letters, vol. 5, no. 2, pp. 641–644, 2013 (Chinese). View at: Publisher Site | Google Scholar
  89. R. Burman, A. A. Strömstedt, M. Malmsten, and U. Göransson, “Cyclotide-membrane interactions: defining factors of membrane binding, depletion and disruption,” Biochimica et Biophysica Acta, vol. 1808, no. 11, pp. 2665–2673, 2011. View at: Publisher Site | Google Scholar
  90. S. T. Henriques, Y.-H. Huang, M. A. R. B. Castanho et al., “Phosphatidylethanolamine binding is a conserved feature of cyclotide-membrane interactions,” The Journal of Biological Chemistry, vol. 287, no. 40, pp. 33629–33643, 2012. View at: Publisher Site | Google Scholar
  91. O. N. Silva, W. F. Porto, L. Migliolo et al., “Cn-AMP1: a new promiscuous peptide with potential for microbial infections treatment,” Biopolymers, vol. 98, no. 4, pp. 322–331, 2012. View at: Publisher Site | Google Scholar
  92. S. M. Mandal, L. Migliolo, S. Das, M. Mandal, O. L. Franco, and T. K. Hazra, “Identification and characterization of a bactericidal and proapoptotic peptide from cycas revoluta seeds with DNA binding properties,” Journal of Cellular Biochemistry, vol. 113, no. 1, pp. 184–193, 2012. View at: Publisher Site | Google Scholar
  93. P. W. Hsieh, F. R. Chang, C. C. Wu et al., “New cytotoxic cyclic peptides and dianthramide from Dianthus superbus,” Journal of Natural Products, vol. 67, no. 9, pp. 1522–1527, 2004. View at: Publisher Site | Google Scholar
  94. A. Wélé, Y. Zhang, I. Ndoye, J.-P. Brouard, J.-L. Pousset, and B. Bodo, “A cytotoxic cyclic heptapeptide from the seeds of Annona cherimola,” Journal of Natural Products, vol. 67, no. 9, pp. 1577–1579, 2004. View at: Publisher Site | Google Scholar
  95. J.-E. Lee, Y. Hitotsuyanagi, I.-H. Kim, T. Hasuda, and K. Takeya, “A novel bicyclic hexapeptide, RA-XVIII, from Rubia cordifolia: structure, semi-synthesis, and cytotoxicity,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 2, pp. 808–811, 2008. View at: Publisher Site | Google Scholar

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