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[email protected] Anti-Cancer Agents in Medicinal Chemistry, 2016, 16, 793-801 ISSN: 1871-5206 eISSN: 1875-5992
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A Review on Novel Breast Cancer Therapies: Photodynamic Therapy and Plant Derived Agent Induced Cell Death Mechanisms Blassan Plackal Adimuriyil George and Heidi Abrahamse* Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein 2028, South Africa
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Abstract: This review article presents an extensive examination of risk factors for breast cancer, treatment strategies with special attention to photodynamic therapy and natural product based treatments. Breast cancer remains the most commonly occurring cancer in women worldwide and the detection, treatment, and prevention are prominent concerns in public health. Background information on current developments in treatment helps to update the approach towards risk assessment. Breast cancer risk is linked to many factors such as hereditary, reproductive and lifestyle factors. Minimally invasive Photodynamic therapy (PDT) can be used in the management of various cancers; it uses a light sensitive drug (a photosensitizer, PS) and a light of visible wavelength, to destroy targeted cancer cells. State of the art analyses has been carried out to investigate advancement in the search for the cure and control of cancer progression using natural products. Traditional medicinal plants have been used as lead compounds for drug discovery in modern medicine. Both PDT and plant derived drugs induce cell death via different mechanisms including apoptosis, necrosis, autophagy, cell cycle regulation and even the regulation of various cell signalling pathways.
Revised: October 22, 2015
INTRODUCTION
Accepted: October 25, 2015
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therapy is the use of plant extracts or phytochemicals [9]. The anticancer drug discovery from plant derived agents initiated in 1950s with the development of vinca alkaloids [10]. Plant derived products are potent sources of novel anticancer drugs and have contributed much in chemotherapy [11]. According to a study, over 50% of anticancer drugs undergoing clinical trials are isolated from plants [12]. The development of anticancer agents from phytochemicals has focused on the molecular mechanism by which it induces toxicity and cell death. Phenolics and flavonoids are known to exert antitumour activity through multilateral mechanisms [13, 14]. Some phytochemicals or their derivatives are photosensitive and employed in the photodynamic therapy of various diseases as natural photosensitisers.
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Cancer begins when cells start to grow out of control and keep on dividing, forming immortal, abnormal cells while invading other tissues [1]. According to the world health organization around 14.1 million individuals were diagnosed with cancer in 2012 among which 8.2 million death were reported worldwide. Breast cancer (BC) is reported to be the most widespread cancer and the foremost cause of cancer deaths in women worldwide [2]. There were about 1.38 million new cases of BC in the year 2008 and by 2020 this figure is likely to escalate to 1.7 million [3]. “Breast cancer” is a collective term for numerous subtypes of cancer of the breast. All differ in their clinical staging, gene expression and molecular characteristics [4]. The different types may have some distinct causes and factors that might impact approaches to prevention [5]. Breast cancer usually originates in the duct or lobes of breast tissues and the ductal cancer is more common (about 85%) than lobular [6]. Inflammatory breast cancer is a comparatively atypical (1 to 6 %) aggressive form with possible quick inflammation and reddening of the breast tissues. These cancer types are all invasive, and can metastasize. The non-invasive forms are ductal or lobular carcinoma in situ. The non-invasive cancers are practically treatable because they have not invaded in to the duct wall [7]. Based on biological markers, breast cancer is classified into: basal, human epidermal growth factor receptor 2 (HER-2) overexpression, luminal A, luminal B and unclassified. The basal is “triple negative” cancer, here the cells are negative for all three hormone receptors (estrogen receptor- ER, progesterone receptor- PR and HER-2). HER-2 over expression tumours are with extra copies of HER-2 gene and over-produce the resulting growth-enhancing protein. Luminal A and B are ER positive; with Luminal A being slow growing compared to Luminal B [8].
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Received: March 16, 2015
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Keywords: Apoptosis, breast cancer, cancer treatment, cell cycle, photodynamic therapy, plant derived agents.
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Plants and plant derived products have been used to benefit human health since antiquity. The foremost part of conventional *Address correspondence to this author at the Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein 2028, South Africa; Tel: (+27) 11 559 6550; Fax: (+27) 11 559 6884; E-mail:
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In photodynamic therapy (PDT), photosensitizers (PSs) are administered systemically or topically. The excitation of the PS from ground state produces singlet oxygen, which destroys cells. The major advantages of PDT are its selectivity, low invasiveness and minor side effects, which are significant for improving the patient’s quality of life [15]. The role of PS is to absorb light energy in form of photons and transfer it to the substrate. The wavelength of light is pertinent to the absorption properties of PS. When the molecular oxygen absorbs excess energy resulting from light contact, singlet oxygen is formed, leading to the damage of cancer cells [16]. Cancer Incidence, Risk Factors and Treatment Modalities Breast cancer risk is related to many factors, which includes hormonal history, exposure to estrogen and progesterone, early menarche and late menopause. All these factors lead to more menstrual cycles and hormone exposure [17]. Phytoestrogens can block estrogen receptors; they do not stimulate proliferation of breast cells as much as body’s estrogens do; so phytoestrogen rich diets can lower risk. A diet too high in calories leads to obesity and increases the risk [18]. Familial BC is considered as a risk if a firstdegree relative develops BC before menopause [19]. Genetics plays a role in BC incidence, but less than 7% of breast cancers are considered hereditary [20]. BRCA-1 and BRCA-2 gene mutations cause 80% of genetic breast cancer [21]. High amounts of radiation, © 2016 Bentham Science Publishers
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Breast tumours can be totally removed by surgical resection during the early stages. Major surgical procedures are lumpectomy, mastectomy and axillary lymph node sampling and removal [23, 24]. Radiotherapy is the treatment with highenergy waves, which destroys cancer cells remaining in the body after surgery and decreases the locoregional relapse. In brachytherapy or internal radiation, radioactive seeds are placed straight into the breast tissue near the tumour [25]. Adjuvant therapy (chemotherapy, hormone replacement therapy and biotherapy) is systemic mode of treatment given after surgery for destroying microscopic cancer cells that might remain in the body as a source of relapse [26, 27]. In many countries complementary medicine is used by breast cancer survivors. Chen et al. [28] reported that above 95% of breast cancer survivors in China used alternative medicine and 75% used plant derived agents. Alternative medicine supplements the body to recover from the sideeffects of other therapies.
Zinc phthalocyanine-(ZnPcSmix) was used as the PS in PDT, which induced programmed cell death in MCF-7 breast cancer cells [42]. The Zinc phthalocyanine induced damage to breast cancer cells and fluorescent microscopy had shown that ZnPcSmix was restricted in both mitochondria and lysosomes, the treated cells reduced viability and proliferation [43]. Manoto and Abrahamse [44] reported the reduction in viability, proliferation and an increase in cytotoxicity via membrane damage in A549 lung cancer cells after laser irradiation of Zn sulfophthalocyanine PS.
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PDT-induced cell death is usually caused by apoptosis, necrosis or autophagy. It has been observed that along with the direct cellular toxicity, vascular shutdown and local inflammatory reactions also contribute to the overall cell death induced by PDT [45-47]. Antitumour activity of PSs is possible by means of direct photodynamic killing of tumour cells [48]. PSs have less noticeable activity without light. Apoptosis is a mechanism that intervene toxicity in the targeted tissue. As PSs typically bind to multiple cell organelles, photodynamic damages may be caused to lysosomes, endoplasmic reticulum (ER), golgi apparatus or mitochondria (Fig. 1). The necrotic destruction by PDT is caused by permanent damage of cell membrane and organelles [49]. Depending on the nature and localization of PS, the initial damage may encompass various molecules, thus resulting initiation of specific death pathway that converge on mitochondria.
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Several reviews had summarized the role of phytochemicals in cancer therapy and chemoprevention. There is an estimate that around 50-60% of cancer patients in the United States use different plant derived agents as complementary and alternative medicine, concomitantly with conventional therapeutic regimens such as chemotherapy and/or radiation therapy [29]. PDT has emerged as a promising therapeutic modality for early and advanced stages of cancer by virtue of its selectivity and preferred localization of PS to the tumour sites [30] leading to the tumour vascular shutdown by thrombosis, haemorrhages and recruitment of inflammatory and immune mediators [31]. Tumour destruction, vasculature shutdown and immune response are key cell death mechanisms in PDT of primary and metastatic tumours. The evident advantages of PDT and plant derived agents over other conventional cancer treatments are its minimal side effects, selective targeting, no drug resistance and reduced toxicity [32-34].
phrotoporphyrin IX (PpIX), which is an intermediate in the heme biosynthesis. The photodynamically inactive, non-selective and safe 5-ALA is intracellularly absorbed by the photodynamically active PpIX for therapeutic purposes [39]. Pp IX is synthesized by all nucleated cells and is detected in the epidermis within 3-8 hours after 5-ALA administration. Animal and human studies have confirmed that Pp IX is eliminated from the body between 24 and 48 hours after administration of 5-ALA and reduces the risk of prolonged photosensitivity. Methyl-aminolevulinate (MAL), an esterified lipophilic derivative of 5-ALA, is highly selective for neoplastic cells than 5-ALA and is transported by passive diffusion. Soon after penetration, MAL is demethylated to 5-ALA, the subsequent metabolic steps occur until the production of Pp IX being the same [36, 40]. In Europe and in the United States, MAL has been approved by Food and Drug Administration (FDA) for the treatments of actinic keratosis lesions, basal cell carcinoma and Bowen’s disease since 2001 and 2004 [41]. Photofrin, a porphyrin family and a hematoporphyrin derivative (HpD) is the first FDA approved PDT sensitizer [38].
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alcohol consumption and tobacco smoking are known to increase the risk of developing breast cancer [22].
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PDT is a highly selective anticancer treatment modality, which uses light and PS in the presence of oxygen and leads to production of toxic side products that kill tumour cells [35]. PDT involves the systemic administration of non-toxic dyes, PS, which specifically accumulate in tumour cells and, following illumination in the presence of oxygen, generates singlet oxygen and reactive oxygen species (ROS) that cause cytotoxicity. The PS is rapidly eliminated from normal tissues and the low pH of the interstitial fluid within the tumours facilitates the selective biodistribution [36]. The PS absorbs light energy and transfers it to the substrate. Lasers are the favoured light source for the treatment as they provide a clear, monochromatic, prevailing source of light that can be focussed and produce a number of photons to treat the site more precisely [37]. Laser is used for treating internal sites, delivered via an endoscope, needles, optic fibres or balloons. The wavelengths and intensity of light required in PDT vary depending on PS and the light of near infrared is prudent, the higher the wavelength, the deeper the penetration into tissue. The major benefit of lasers in therapy is the option of transferring the light through optical fibers, thus providing a possibility of treating tumours in hollow organs [15]. The high quantum yield for singlet oxygen generation, pure chemical formulation and efficient accretion are the core features of an ideal PS. PSs are stable with short half-lives, easily delivered and can be metabolised and excreted upon the completion of treatment [38]. Hematoporphyrin (Hp) and hematoporphyrin derivatives (HpD) are the first systemic PSs used in medical studies. 5-Aminolevulinic acid (5-ALA) is a clinically approved precursor of natural PS
A number of pro-apoptotic and antiapoptotic factors have been identified. Bcl-2 localizes to mitochondria, endoplasmic reticulum, nucleus and inhibits mitochondrial cytochrome c (cyt c) release and thereby inhibits cell death [50]. Mitochondria and lysosome localized sensitizers can cause instant and light-dependent damage to components, such as antiapoptotic and apoptosis-related proteins, stimulating the release of caspase-activating molecules. Some compounds that localize within mitochondria or ER endorse apoptosis, whereas on cell membrane or lysosomes can delay apoptosis and stimulate necrosis [51]. PDT induces apoptosis [49] in cultured cells and in vivo, whereas at higher doses, it leads to necrosis. The mode of cell death depends on various incubation times and site of localization of PS [52]. Mitochondria and Lysosomes as the Targets of PDT A unique feature of PDT induced apoptosis is the agility of cell death [53]. PDT generates reactive oxygen species (ROS) within the mitochondria and causes failure of membrane potential and releases pro-apoptotic factors with subsequent stimulation of caspase cascade leading to the programmed cell death [54, 55]. During
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Fig. (1). PDT induced cell death; possible mechanisms. PDT targets lysosomes, mitochondria, endoplasmic reticulum (ER) and cytoskeleton. Upon PDT, lysosomes release cathepsin which induces apoptosis via caspases activity. The proteolytic activity of lysosomal extract cleaves Bid to tBid and leads to mitochondrial pore opening via Bax action. Mitochondrial membrane potential drop off by PDT, and releases cyt c leading to direct cell death via caspases action. ER releases Ca2+ causes mitochondrial pore opening and activation of calpain pathway both leads to apoptosis. The plasma membrane damage after PDT is leads to the reduction of active transport, depolarization of plasma membrane, lipid peroxidation and generates singlet oxygen; as it contains the death receptors which also help in the activation of death signals thereby inducing the cell death.
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PDT, only the cells with procaspase-3 will be able to activate caspase-3 and caspase-9, cleave poly (ADP-ribose) polymerase (PARP), fragment DNA, and condense chromatin to generate apoptotic bodies. The intrinsic apoptotic cell death is competently induced in mitochondria by PDT [56]. The mitochondrial association of Porphyrin-derived PSs can induce apoptotic cell death. Upon light activation, PS initiates the cyt c release. Cytosolic cyt c activates caspase-9, 3, 6, and 7. Caspase 3 can also process caspase8 to enhance cyt c discharge by cleaving Bid, a proapoptotic member of Bcl-2 protein family. Cellular redistribution of Bax may also increase cyt c release in some cells during PDT [54]. There are many PSs that specially bind to lysosomes and initiate apoptosis. In 1993, lysosomes were considered to be vital targets for PS localization [57]. However, following studies [58] showed that though lysosomally localized PS can lead to cell death, the relative effectiveness is considerably lower than that seen with PS restricted in mitochondria and other cell organelles [59]. The lysosomal extract contains proteolytic activity and is capable of cleaving Bid. Although cathepsins reside in lysosomes and to be released upon lysosomal damage, the inhibitors of cathepsins B, D, and L were unable to block PDT initiated apoptosis [60, 61]. The cationic hydrophobic PS specially localizes in mitochondria [62] mainly because of the membrane potential and lipid bilayer of the membrane [63].
Endoplasmic Reticulum and Cytoskeleton as PDT Targets Photoactivation in turn activates different heat shock proteins and ER chaperones leading to caspase-12 mediated apoptosis [64]. PDT also causes photodamage to the sarcoplasmic/ER calcium pump. The cell membrane contains Ca2+ transporters with reduced state thiol groups, which properly maintain the level of intracellular Ca2+. PDT damages the membrane proteins, which causes dysregulation of intracellular Ca2+ [65]. Several studies reported that PDT increases the level of cytosolic free Ca2+ in numerous cells. Calcium ions released from photodynamically damaged ER stimulates mitochondrial bulge, cyt c release and depending on the damage level either apoptosis or necrosis can be commenced [66]. Cell cytoskeleton is an important target of PDT [67]. The 5ALA mediated PDT directed to damage of cytoskeleton due to the alteration of actin filaments with the downfall of adapter proteins, Cofilin phosphorylation and leading to the depolymerisation of actin [68]. PDT reduces cell attachment; some benzoporphyrin derivative-monoacid ring and 5-ALA PS hinder the cell connection to substratum [69]. Instant cell membrane damage after PDT is established as swelling, bleb formation, reduction of active transport, detachment of vesicles containing cell membrane, cytoplasmic enzymes and increased permeability to chromate thereby inducing the cell death [70-72].
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PDT and Breast Cancer Treatment
Plants as Anticancer Drugs
Breast cancer is a significant oncological issue diagnosed in more than a million patients every year. The tendency for treatment has turned to breast preservation. PDT had considerable success and an extended history in the treatment of primary and metastatic malignancies. PDT has the extra benefit of being a potentially painfree outpatient procedure, which can work with other treatments or as a stand-alone therapy [73]. The effect of PDT is evident in chest wall recurrences in breast cancer, which follows the histological confirmation of lesions. PDT to the primary tumour might be successful [74] via using drug at comparatively very small doses in between the normal and tumour cells. The local control over the recurrence can be improved by bringing PDT to tumour tissues with a margin of 1-2 centimetres. The non-ionizing laser therapy can be used to eliminate the difficulties and threats of secondary tumours. The current radiation therapy used in the treatment of breast cancer is usually very costly compared with PDT. The internal radiotherapy is time consuming also needs more number of visits, whereas PDT requires a single visit. PDT during the time of lumpectomy also minimizes the treatment time, in contrast to more visits for radiation therapy, which also progresses the long-term local control. It is important to highlight that patients undertaking chemotherapy will have whole breast radiotherapy for many weeks likely to increase local failure rates. PDT might reduce local failure as this is a conventional approach to a novel treatment [75, 76].
Mechanism of Natural Products Mediated Cell Death The major factors related to cell death mechanism include cell cycle halt through up-regulation of p53 and p21, down-regulation of cdk2, cyclin E and E2F-1, and induction of apoptosis via Bax and caspase-7. The plant derived sources for the anticancer treatment act through various mechanisms such as the regulation of various signalling pathways, cell cycle alteration or apoptosis to induce the cell death (Fig. 2). Epidemiological data showed that fruits and vegetables consumption reduces the risk of developing many cancers since they are the store houses of vitamin C and b-carotene [77]. Plants polyphenolics own a wide variety of activities such as antitumour, antiviral, antibacterial and antimutagenic [78]. Cell Signalling
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Nuclear Factor Kappa Beta (NF-KB), a protein complex that regulates the transcription of DNA along with other transcription factors associated with angiogenesis and growth of cancer cells [79]. Ginseng plant extracts found to prevent the lung cancer growth through the regulation of NF-KB signaling pathway. Genistein, a natural isoflavonoid phytoestrogen decreases NF-KB activation by DNA-damaging agents and tumour necrosis factoralpha, also reduces the phosphorylation of inhibitory protein I kappa B alpha and blocks the nuclear translocation of NF-KB. The
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Fig. (2). Plant derived agents induced cell death; possible mechanisms. Anticancer agents interfere with NFKB/PGF/EGF/MAPK/COX-2 signalling pathways, activate JNK/AKT and lead to cyt c release from mitochondria, inhibit Bcl2: Bax interaction further proceeds to apoptosis via caspases cascades. These agents also induce cell cycle arrest in G1 phase through up regulation of p53, p21 and down regulation of Cyc D1/ Cdk4 and Cdk2/ Cyc E thereby leading to the Rb resulted inactivation of transcription factor E2F. Which controls the estrogen mediated cell cycle in S phase by regulation Cyc E-Cdk2/ D1-Cdk4, interferes with microtubules and causes M phase arrest.
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Apoptosis and Autophagic Cell Death It was also observed that different plant derived compounds varied in their target of action in bringing about cell death. Some reports showed that apoptosis induction is related with the regulation of pro-apoptotic and antiapoptotic proteins. Terminal kinases regulate the activity of Bcl-2 family proteins [104]. Phosphorylation of Bcl-2 has been connected with the practical inactivation of antiapoptotic proteins. Bad, is a proapoptotic member and its phosphorylation demonstrated to abolish Bcl-2 mediated proapoptotic activity [105]. One of the important roles of protein kinase B or AKT is to phosphorylate Bad, which causes cytoplasmic sequestration [106]. Xiao et al. [107] stated that diallyl trisulfide reduced the expression of antiapoptotic proteins (Bcl-2) and elevated hyperphosphorylation of this protein through JNK activation, which further reduced Bcl-2: Bax communication, thereby inducing the caspase-3,-8, and -9 activities.
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Cell cycle switch has been established as a key event in confirming the accuracy of cell division and the defects in cell cycle have been related with carcinogenesis. Thus, cell cycle regulators could be targeted for chemoprevention and has become appreciated targets for management and treatment of tumour cells [83]. The checkpoints in G1, G2 phases cause the continuation of cell cycle in regular way. Cancerous cells are not capable of pausing at the checkpoints (G1/S and G2/M) and therefore proliferation becomes deregulated [79]. Plant derived antitumour drugs stop cell cycle at different phases (G0/G1, S, or G2/M) and prompt programmed cell death pathway [85-91]. Some drugs (vinca alkaloids and taxanes) interfere with microtubules and prevent alignment of the daughter chromosomes and consequently lead to stop mitosis, which can be finally followed by apoptosis. Several herbal drugs (camptothecins and epopodophylotoxins) act as topoisomerase I and II inhibitors, which control topoisomerase activity leading to the cell death [92]. The phytoestrogens are strong inhibitors of protein tyrosine kinase and DNA topoisomerase II activities. The inhibitory effects of these isoflavonoids on cell proliferation were associated with a G2/M cell cycle arrest with a noticeable inhibition of cyclin B1 and an induction of Cdk inhibitor p21 in a p53-independent manner. Genistein treatment showed an increased binding of p21 with Cdk2 and Cdc2 with a significant decrease in Cdc2 and Cdk2 kinase activity. Many phytoestrogens possibly induced the activation of p21 and the downregulation of kinase activities of Cdks and related cyclins, leading to G2/M arrest in the cell cycle [93, 94].
The mitochondrial pathway is the key apoptotic mechanism due the cytosolic cyt c. The apoptosis-inducing Bax led to mitochondrial dysfunction and releases cyt c, further which complexes with other apoptosis inducing factors [108, 109]. The activation of caspase leads to degradation of many cellular proteins, cell shrinkage, DNA fragmentation, loss of membrane potential and blebbing [110]. Cysteine proteases (caspases) cleave the DNA repair Poly ADPRibose Polymerase (PARP) enzyme and maintain the genome integrity. Homeostasis is a balance between cell proliferation and apoptosis [111]. One of the most important features of tumour cells is the loss of homeostasis; dietary manipulation might bring awareness into cancer prevention through this process [112]. Many dietary phenolics, such as resveratrol, curcumin and epigallocatechin have showed anticancer activities via apoptosis induction through the downregulation of Bcl-2 proteins leading to the mitochondrial damage and subsequent caspase dependent apoptosis [113].
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Polypeptide growth factors and epidermal growth factors attach to their specific receptors resulting via protein tyrosine kinase signal transduction leading to the formation of neoplasms. Plant extracts act by blocking the expression of these growth factors and receptors. The mitogen activated protein kinase (MAPK) stimulation induces signals for the proliferation of cells. The deregulation of MAPKs by Zengshenping was involved in anticarcinogenesis via apoptosis [79, 81]. The MAPK activation is regulated by a hierarchical MAPK cascade. Mitogens such as growth factors, cytokines, and environmental stress naturally activate MAP3Ks, which subsequently results in MAP2K phosphorylation. The phosphorylated MAP2Ks activate terminal MAPKs such as Erk1/2, p38, and JNK/SAPK. The chemopreventive dietary phytochemicals can activate MAPK pathway, leading to gene expression, apoptosis and differentiation of cancer cells. The inhibition of cyclooxygenase-2 (COX-2) pathway and blocking the prostaglandin by plant extracts cascade might affect the growth of malignant cells through inhibiting the proliferation and angiogenesis [83]. Since COX-2 is one of the pro-inflammatory mediators, which may be induced at the early stage of carcinogenesis. COX-2 is normally low in most cells but is constitutively elevated in cancers and therefore COX-2 is proposed to be a nutritional target for cancer chemoprevention. The prevention of the abnormal expression of COX-2 could stop the formation of cancer because of its insurgence [84].
cyclin-dependant kinases [98, 99]. The expression of p21 and p53 appears to be significant where tumours with both genes were less destructive than those expressing any one [100]. Moreover, estrogen stimulates cyclin E-cdk2 and cyclin D1-cdk4; significantly preceding entry into S phase [101]. Licorice root extract prevent the breast and prostate cancer cell growth by blocking cell cycle at various phases. The plant extracts are capable of inducing G1 arrest, which may be facilitated through expression of p21 and downregulation cyclin E/cdk2. Curcumin decreases the expression of EGFR, activity of p21-activated kinase (PAK) 1, a downstream regulator of EGFR and PAK1 regulated NF-κB activity leading to the decrease in cell proliferation by reducing the cyclin D1 mRNA and protein expression and arrests the cell cycle at G1 phase [102, 103].
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mechanism by which genistein induces apoptosis in cancer cells is the inactivation of NF-KB, which strongly supports its role as a natural chemopreventive agent [80, 81]. NF-KB inactivation with genistein is linked with down regulation of AKT. This suggests that blocking the interactions of AKT and NF-KB is the way by which genistein induces its mechanism of cell death [82].
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The cyclins, a group of proteins that trigger the cell cycle dependent kinases (Cdks) that control the progress in cell cycle [95]. The p21 overexpression associated with inhibition of cyclinCdK4 complexes. The G1 arrest and induction of apoptosis may be controlled through the up regulation of p21, also the down regulation of cyclin D1 and CdK4 [96, 97]. The observation of a G0/G1 arrest on treatment with plant extracts suggest the antitumour effect would be through the regulation of p53 or the
Even though apoptosis has been the most studied cell death mechanism, it is not the only response. Autophagic cell death has recently been described as an alternate mechanism. Autophagy may also be followed by apoptosis in certain situations, especially when the cells have an active caspase-3 [114]. A number of plant derived compounds such as camptothecin, oridonin have shown to induce autophagic cell death by caspase 3 expressions [115, 116]. The link between cell cycle arrest and autophagy has also been reported; p27 inhibits cyclin-dependent kinase activity and defects in Cdk2- and Cdk4-increased autophagy. Induction of autophagy has been observed to reduce cellular levels of p53 leading to the G1 phase cells accumulation [117, 118]. Plant Derived Agents for Breast and other Related Cancer Treatments Plants such as Cassia auriculata [119], Inula lineariifolia [120], Pereckia bleo [121], Phyllanthus amarus [122], Terminalia chebula [123], Sclerocarya birrea [124], Pandanus amaryllifolius [125], Mangifera pajang [126], Dillenia suffruticosa [127], Ziziphus
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CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
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ACKNOWLEDGEMENTS Declared none.
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REFERENCES [1]
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Cancer is one of the foremost causes of death while breast cancer is the malignant tumour of breast cells and the most serious life threatening oncological issue among women globally. Conventional treatments such as surgery, radiotherapy and adjuvant therapies continually destroy the dividing malignant cells but also affect normal cells. Alternative medications and treatment strategies have been investigated to overcome or to reduce this serious health issue. Recently, the advent of plant derived anticancer agents and use of photodynamic cancer therapy has improved the prognosis for breast cancer patients. Various plants extract and phytochemicals or analogues have been used for decreasing the number of cancer cells by inhibiting cell proliferation rate and inducing the cell death. Even at very low concentrations, many compounds are able to enhance programmed cell death pathways whereas high concentrations have direct toxic effects, leading to rapid necrosis. Photodynamic therapy is a novel therapy for cancer, with a promising less-invasive alternative for the adjuvant treatment modules. Possibly, PDT could be effectively used in the treatment of chest wall metastasis to increase local tumour control and inhibit the spreading to lymphatic system and other organs. Since PDT is highly effective on later stages of recurrences, it could be introduced initially rather than as a last option in the treatment paradigm. Due to the high success rate in the area of anticancer chemotherapy, natural products may be a potential candidate for therapeutic agent along with PDT for the control of breast and related cancers by regulating the cell signalling, cell cycle alteration, apoptotic or even autophagic cell death.
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CONCLUSION AND FUTURE PERCEPTION
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jujube [128], Brucea javanica, Azadirachta indica [129] have been reported for their cytotoxicity, cell cycle inhibition and apoptotic induction in human breast and other related tumour cells. The extracts of Rubus ellipticus [130], R. niveus [131] and R. fairholmianus [132] have been reported for its antitumour properties and the isolated bioactive compounds of R. fairholmianus possessed in silico antiproliferative activities against BRCA1 and BRCA 2 breast cancer target proteins [133]. The plant derived agents such as curcumin [119]; sesquiterpenoids [120], nimbolide [134], carvacrol [135], lectin [136], methylanthraquinone [137] also found to induce apoptosis in various kinds of breast cancer cells. The main natural derived anticancer therapeutics are tubulin-binding agents such as vinca alkaloids, microtubule destabilizing agents, taxanes and microtubule stabilizing agents, topoisomerase inhibitors such as camptothecins, epipodophyllotoxins and anthracyclines [92]. The most significant plant derived anticancer agent vinca alkaloids (vincristine and vinblastine) are isolated from Catharanthus roseus [138]. Paclitaxel, camptothecin derivatives, irinotecan and topotecan, obtained from the bark and wood of Camptotheca accuminata can be employed in the treatment of colorectal and ovarian cancer, stabilizing microtubules, leading to mitotic arrest and inhibiting topoisomerase I [139]. Flavopiridol is a synthetic flavone derived from Amoora rohituka, interferes with the phosphorylation of cyclin-dependent kinases, hindering their activation and blocking cell cycle progression at G1 or G2 phase [140].
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