Isothiocyanates and Its Impacts on Female-Specific Cancers: History
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Contributor:
Shoaib Shoaib
,
Farheen Badrealam Khan
,
Meshari A. Alsharif
,
M. Shaheer Malik
,
Saleh A. Ahmed
,
Yahya F. Jamous
,
Shahab Uddin
,
Ching Siang Tan
,
Chrismawan Ardianto
,
Saba Tufail
,
Long Chiau Ming
,
Nabiha Yusuf
,
Najmul Islam

Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers.

  • Isothiocyanates
  • sulforaphane
  • benzyl isothiocyanate
  • phenethyl isothiocyanate

1. General Characteristics, Sources, and Biological Importance of Isothiocyanates

In the last few decades, there has been a growing interest in utilizing the potential of various phytochemicals in the fight against various pathological conditions [1][2][3][4][5][6][7][8][9][10][11][12]. Interestingly, both in vitro and in vivo studies have enlightened their potential against many disease pathologies, including metabolic, inflammatory, neurodegenerative, cardiovascular diseases, cancer, and so on [13][14][15][16][17][18][19][20][21]. Furthermore, a considerable number of studies provided proof of the health benefits of various dietary phytochemicals [22][23]. Of note, it is reasonable to argue that over the last two decades, bioactive compounds have gained great attention as therapeutic interventions against diverse disease conditions, either as solitary treatment and/or in combinatorial treatment regimens [24][25]. Concomitantly, with tremendous efforts laid down for scientific verification of pharmacological actions of various phytochemicals, and verification/validation of the basis of the use of these phytochemicals in the treatment of diseased conditions, including cancer, it is envisaged that they are not far from bringing therapeutic revolution.
In general, bioactive phytochemicals can be classified into various groups, including organosulfurs, phenolics, alkaloids, terpenoids, chalcones, glycosides, coumarins, etc. ITCs are the products of enzymatic hydrolysis of glucosinolates present in plants of the Brassicaceae family, and as secondary metabolites, they have been identified for their wide range of biological properties, including anticarcinogenic, antimicrobial, antioxidant, anti-inflammatory, and so on [26][27][28].

2. Impacts of Isothiocyanates on Female-Specific Cancers

Accumulating evidence indicates that cruciferous plants possess many bioactive phytochemicals which have been identified as potential chemopreventive agents [29]. In particular, cruciferous ITCs have been shown to considerably alter the cellular activities occurring during carcinogenesis [30]. Given that the bioactive phytochemicals, particularly ITCs play crucial role in modulation of molecular mediators of carcinogenesis [31], the extending data implies the importance of ITCs in the form of intriguing pharmacological interventions [32]. A significant number of reports have demonstrated that ITCs actively participate in modulation of various cellular processes, including the modulation of cancer cell proliferation, migration and invasion, cell cycle arrest, apoptosis induction, and modulation of autophagy and cancer stem cells (CSCs) [33].

2.1. Impacts of Isothiocyanates on Cancer Proliferation, Migration, and Invasion-Related Signal Transduction Pathways

As a matter of fact, human cancers are basically characterized by frequent abnormalities in the signal transduction pathways that regulate cellular proliferation and survival. As a matter of fact, one of the oncogenic signal transduction pathways is PI3K/Akt/mTOR/S6K1, a pro-survival signaling pathway, often found to be hyperactive due to constitutive activation of PI3K or Akt and/or loss of PTEN (a negative regulator of the PI3K/Akt/mTOR/S6K1 pathway) [34][35]. Basically, the PI3K/Akt/mTOR/S6K1 pathway mostly contributes to uncontrolled cell proliferation, migration, neovascularization, and evasion of apoptosis, and occasionally mutations in Akt may also lead to chemoresistance.

2.1.1. Impacts of SFN on Cancer Proliferation, Migration, and Invasion-Related Signal Transduction Pathways

Interestingly, molecular studies have demonstrated that SFN considerably inhibits the survival of MCF-7, MDA-MB-231, MDA-MB-238, and SKBR-3 breast cancer cells in a dose-dependent manner, seemingly through attenuation of phosphorylation of Akt and S6K1 [36]. Furthermore, it was found that SFN significantly inhibited the growth, proliferation, and colony formation in MCF-7 and MD-MB-231 cells, without having any effects on the non-tumorigenic cells viz MCF-10A [36]. Moreover, as a matter of fact, DNA methyltransferases (DNMTs) which are required for DNA methylation, play an important role in the normal development of mammalian cells plausibly through the maintenance of genomic stability. However, aberrant DNA methylation, seemingly due to hyper-activation of the DNMTs, has been closely linked with many cancers. To this end, it was found that SFN treatment seemingly leads to suppression of human telomerase reverse transcriptase (hTERT) expression and DNA methyltransferases (DNMT1 and DNMT3a) that correlates with demethylation of the exon 1 region of the hTERT promoter and the binding of a transcription factor, CTCF to hTERT, leading to repression of hTERT transcription in MCF-7 and MDA-MB-231 cells [37]. Concomitantly, SFN-treated MCF-7 and MDA-MB-231 cells corroborated decreased viability and proliferation inhibition in a dose- and time-dependent manner [38]. Another study also showed that SFN conferred cytotoxicity on breast cancer cells (MCF-7, MDA-MB-231, MDA-MB-468, and T47D) in a time- and dose-dependent manner [39]. Furthermore, transcriptional regulation of hTERT is considered to activate telomerase in human cancers, which maintains or lengthens telomeres, and hTERT up-regulation is mostly achieved by genetic and epigenetic alterations. To this end, it has been found that SFN treatment inhibited hTERT in a dose- and time-dependent manner [37]. Furthermore, the balance between the activity of histone acetylation and deacetylation, which is achieved by histone acetyl transferases (HATs) and histone deacetylases (HDAC), is very critical for the normal functioning of the cells. However, variations in the expression of HDACs or mutations in their genes have been correlated with the development of different cancers [40]. Interestingly it was reported that SFN treatment leads to the inhibition of global HDAC activity, as also discussed below [39]. Furthermore, studies have shown that SFN triggered both single- and double-stranded breaks, leading to elevated phosphorylation of Ataxia-telangiectasia mutated (ATM), a protein kinase regulating DNA damage responses, and its expression results in the suppression of cancer growth, migration, and invasion [41][42][43]. Intriguingly, it is widely accepted that the cross-talk between histone deacetylase (HDACs) and lysine-specific demethylase 1 (LSD1) facilitates cancer cell growth and proliferation, and interestingly, it was demonstrated to be prevented following SFN treatment in MDA-MB-231 cells [44].
Furthermore, it has been highlighted that SFN treatment considerably suppressed the dynamic instability behavior of purified microtubules, which indicates that SFN-mediated cytotoxic effects on breast cancer cells were due to direct action on the microtubules as well [45]. Another study was conducted on KPL-1 breast cancer cells, wherein SFN treatment resulted in the growth inhibition of these cells in a dose- and time-dependent manner. Additionally, it suppressed the growth and metastasis of orthotopically transplanted KPL-1 cells in female athymic mice [46]. Furthermore, a study highlighted that SFN considerably suppressed proliferation of MCF-7 cells at IC50 of 12.5 and 7.5 µmol following 24 h and 48 h treatment, respectively, and this aspect was linked with the inhibition of estrogen receptor alpha protein together with inhibition of progesterone receptor [47].
Moreover, SFN-treated MDA-MB-231, MCF-7, and SKBR-3 cells exhibited a decrement in the viability of metabolically active cells in a dose-dependent manner, whereas no such effects were observed on HMEC normal cells [41]. The key cellular regulator responsible for the SFN cytotoxic effects was the induction of oxidative and nitrosative stress; since SFN treatment led to intracellular and mitochondrial ROS generation, protein carbonylation, and nitric oxide production in all breast cancer cell lines [41].
As a matter of fact, Wnt/β-catenin pathway activation is associated with the regulation of embryonic development and other physiological processes, while aberrant activation of this pathway results in the increased expression of β-catenin protein that augments metastasis, self-renewal of cancer stem cells (CSCs), chemoresistance, neovascularization, and immune evasion [48]. To this end, one of the studies showed that SFN down-regulated the Wnt/β-catenin pathway, resulting in considerable inhibition in cell viability and apoptosis induction in MCF-7 and SUM159 cells [49].
Over the years, studies have shown that SFN significantly exerted cytotoxic effects on cervical cancer cells (HeLa, Cx, and CxWJ) seemingly by promoting proliferation inhibition [50]. SFN induced growth inhibition in HeLa cells in a dose-dependent manner through apoptosis induction and reduction in inflammation-related proteins [50]. Another study found that SFN modifies epigenetic events causing cervical cancer. It was found that SFN reactivates tumor suppressor genes (TSGs) via inhibition of HDAC1 and DNA methyltransferase (DNMT3B) in human cervical cancer cells (HeLa) [51]. SFN has been shown to inhibit HeLa cell viability by apoptosis induction, as observed by the formation of apoptotic bodies and an increase in the sub-G1 cells [52]. Likewise, another interesting study reported that SFN exerts dose-dependent cytotoxicity against HeLa cells mediated by apoptosis and the anti-phlogistic effect [53].
Uncontrolled growth of cancer cells results in hypoxic conditions leading to the activation and transport of hypoxia-inducible factor-1α (HIF-1α) into the nucleus from the cytosol, wherein it acts as a transcription factor and promotes the expression of genes encoding for glucose transporter and angiogenesis-related proteins that influence glycolytic metabolism, cell growth, survival and angiogenesis thereof [54]. To this end, an in vitro study highlighted that SFN decreased the expression of HIF-1α and GLUT-1, suggesting SFN can efficiently inhibit HIF-1-mediated proliferation and migration in A2780 and A2780/CP ovarian carcinoma cells [55]. Moreover, the role of oncogenic c-Myc (transcription factor) has been investigated in many cancers, and in particular, oncogenic expression of c-Myc is activated by aberrant upstream signaling, super-enhancer activation, chromosomal amplification, and translocation, resulting in cell proliferation and chemoresistance. Targeting the expression of c-Myc may lead to considerable inhibition of cancer cell proliferation and enhanced sensitization of cancer drugs to chemoresistant cells [56]. Previously, one study highlighted that SFN considerably inhibits OVCAR-3 and A2780 cell growth, proliferation, colony formation, and metastasis. Further exploration of the mode of action highlighted that SFN-mediated cytotoxicity occurred in response to the suppression of c-Myc along with the inhibition of Akt and NF-κB thereof [57]. SFN-exposed SKOV-3 and OVCAR-3 cells demonstrated concentration-dependent decrement in the cell density following 48 h of exposure, seemingly through induction of apoptosis [58]. Moreover, dose- and time-dependent anti-proliferative effects of SFN were observed at IC50 of 40 µmol/L for SKOV-3, and 25 µmol/L for C3 and T3 cells, respectively [4]. SFN was very effective in inhibiting the clonogenicity of these ovarian cancer cells and also caused nuclear fragmentation and cellular morphological changes in SKOV-3, C3, and T3 cells [4]. Another in vitro study indicated that SFN inhibited PA-1 ovarian cancer cells in a dose- and time-dependent manner [59]. Moreover, SFN decreased the viability of MDAH2-774 and SKOV-3 ovarian cancer cells in a time- and dose-dependent manner, and the study highlighted considerable cellular morphological changes in these treated cells [60]. Of note, NF-κB is a transcription factor that has been studied extensively, and the emerging data indicate that NF-κB has multiple activators, including epidermal growth factor receptor (EGFR) and TNF-α. Evidence has shown that the activation of NF-κB has been linked with cancer cell proliferation, survival, metastasis, inflammation, neovascularization, and chemo- and radioresistance [61][62]. These aspects highlight that NF-κB could be a valuable pharmacological target for therapeutic intervention against cancer. Different points in the NF-κB pathway have been targeted to inhibit and/or regulate NF-κB activation. In the past few years, much effort has been devoted to the development and characterization of NF-κB blocking agents, including natural as well as synthetic compounds. A significant amount of progress has been made in the preclinical and clinical studies, and some anticancer compounds with NF-κB-inhibiting properties, such as bortezomib, are already being used clinically. Interestingly, but not surprisingly, it has been highlighted that SFN can strongly inhibit the NF-κB signaling pathway in breast carcinoma cells and considerably attenuates 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced Matrix metalloproteases (MMP-9) expression thereof. Collectively, the study explicitly demonstrated that SFN significantly suppresses TPA-stimulated cancer cell invasion; thus, it could be a prospective candidate for the development of intriguing therapeutics for the prevention of breast tumor invasion and metastasis in the in vivo model [63].

2.1.2. Impacts of BITC on Cancer Proliferation, Migration, and Invasion-Related Signal Transduction Pathways

Over the years, studies have shown that BITC suppressed the growth of MCF-7 and MDA-MB-231 cells through apoptosis induction and cell cycle arrest [64]. The altered expression of EMT-associated proteins, the increased expression of E-cadherin, and occludin with concomitant down-regulation of Snail, vimentin, fibronectin, and c-Met supported the declined epithelial–mesenchymal transition (EMT) potential [65]. An in vitro and in vivo study also indicated that BITC efficiently inhibited EMT, migration, and invasion, owing to repression of urokinase-type plasminogen activator (uPA) in breast cancer cells [66]. In an in vitro study, in addition to DNA fragmentation, the number of Annexin-V and propidium iodide-positive cells was demonstrated to be increased following treatment with BITC, indicating apoptosis induction in HeLa cells, which was further correlated with the decreased ATP level [67]. The mechanistic insights highlighted that BITC treatment resulted in the increased production of ROS, which led to caspase-3 activation in HeLa cells. BITC exposure to HeLa and MRC-5 cells decreased cell viability in a time- and dose-dependent manner [68]. Furthermore, BITC treatment was more toxic to the dividing cells, owing to reduced phosphorylation of Aurora A [68]. BITC-treated ovarian cancer cells undergo growth and proliferation inhibition in a dose- and time-dependent manner, seemingly due to the induction of DNA fragmentation, condensation, and eventually apoptosis induction [69]. As a matter of fact, Notch2 is a Notch receptor that is frequently overexpressed in a variety of malignancies and is associated with a distinct carcinogenic process. Evidence has shown that the Notch2 receptor has been targeted by several plant products, and one such study highlights that Notch2 activation by BITC impedes its inhibitory effect on breast cancer cell migration [70].

2.1.3. Impacts of PEITC on Cancer Proliferation, Migration, and Invasion-Related Signal Transduction Pathways

It is widely acknowledged that neovascularization is a critical step in the progression of tumor growth and metastatic dissemination. As a result, the molecular basis of neovascularization has piqued the curiosity of cancer researchers. One of the primary regulators of this process is the vascular endothelial growth factor (VEGF) pathway. Once the VEGF-receptor pathway is triggered, it, in turn, activates multiple signal transduction pathways resulting in the promotion of endothelial cell proliferation, migration, and neovascularization [71]. Therefore, many of the bioactive phytocompounds have been explored in order to block aberrant expression of VEGF to control and prevent cancer. One such phytocompound is PEITC, which exerted cytotoxic effects primarily through the extensive generation of reactive oxygen species (ROS), leading to the decreased expression of hypoxia-sensitive HIF-1α protein and heat shock Hsp90 protein, which further attenuated the expression of MMP2, MMP9, and VEGF to attenuate cellular adhesion, migration, and invasion of MCF-7 and MDA-MB-231 cells [72]. Notably, the same study indicated that PEITC also enhanced nuclear accumulation of the nuclear factor erythroid2-related factor2 (Nrf2) that acts as a master switch to the regulation of redox homeostasis. Moreover, PEITC suppressed MDA-MB-231 and MCF-7 cells by inducing DNA fragmentation that resulted in apoptosis induction and cell cycle arrest thereof [73]. PEITC treatment suppressed cell viability of MDA-MB-231, T47D, BT549, MCF-7, SKBR3, and ZR-75-1 at IC50 concentrations of 7.2 µmol, 9.2 µmol, 11.9 µmol, 10.6 µmol, 26.4 µmol, and 40.4 µmol, respectively [74].
Oncogenic activation of mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway may occur in response to the upstream genomic events as well as by activation of other multiple-associated signaling pathways. Especially, hyperactivation of MAPK/ERK1/2 mostly results in cancer development and progression as the pathway help in the survival, proliferation, and metastatic properties of cancer cells [75]. An in vitro study displayed that treating breast cancer cells with PEITC abrogated MAPK/ERK1/2 signaling pathway and down-regulated estrogen receptor (ER-α36), leading to the growth inhibition of breast cancer cells [76]. Furthermore, PEITC treatment resulted in the restoration of normal p53 checkpoint control pathway in mutant p53-expressing cancer cells, which normally functions to inhibit cell transformation, and its inactivation has been correlated with tumor cell growth and survival [77]. Moreover, PEITC exerted a significant cytotoxic effect on BRI-JM04 cells derived from a mammary tumor of an MMTV-neu transgenic mouse, seemingly through nuclear fragmentation and cleavage of poly (ADP-ribose) polymerase (PARP) [78]. Furthermore, PEITC down-regulated cadherin 1 by attenuating DNMT and HDAC activities, which further suppressed Wnt/β-catenin signaling, limiting colony formation and the growth of breast cancer cells [79].
Of note, CD44 hyperactivation has been reported in many cancers, and binding of CD44 with hyaluronan ligand results in oncogenic activation of signaling pathways which endorse induction of cell proliferation, migration, survival, EMT, and adaptive cancer plasticity [80]. One other such signaling molecule is ICAM1, which is localized at the cell surface as a receptor glycoprotein, and several studies have identified ICAM1 as a key signaling molecule contributing to cancer cell proliferation, migration, invasion, and neovascularization [81]. Thus, CD44 and ICAM1 both have been studied extensively as selective therapeutic targets in the field of cancer therapy and prevention. It has been envisaged that PEITC treatment resulted in the down-regulation of CD44, ICAM1, and also MMPs (MMP2 and MMP9), which further promoted suppression of invasion and migration of HeLa cells [79]. PEITC also showed significant growth inhibitory effects on cervical cancer cells by inducing apoptosis in HEp-2 and KB cervical cancer cells [82]. Of note, the transforming growth factor-β (TGF-β) is a receptor protein that has been documented to control several cellular processes, and TGF-β, upon binding with its ligand, results in the phosphorylation of SMADs; thereby, phosphorylated SMADs translocate to the nucleus to induce the transcription of several genes which foster oncogenic cellular processes including proliferation, evasion of apoptosis, EMT, and metastasis in late stages of cancer [83]. Interestingly, PEITC was reported to down-regulate TGF-β and Smad2 signaling, which accompanied alterations in the expression of metastasis-associated signaling molecules in HeLa cells [84]. Furthermore, another study demonstrated that PEITC exerted significant cytotoxic effects on Caski and HeLa cells in a dose- and time-dependent manner through the production of intracellular and mitochondrial ROS [85]. Additionally, the study also demonstrated that PEITC treatment caused significant alterations in the morphology of CaSki and HeLa cells, whereas not many significant alterations in the morphology of HaCaT cells (normal skin cell line) were observed [85].
Of note, signal transducers and activators of transcription (STAT3) are recognized as important regulators of various biological processes such as cell migration, survival, neovascularization, apoptosis, and cell cycle progression [86]. In this direction, numerous researchers have highlighted STAT3 as a potent therapeutic target for different phytocompounds such as polyphenols, organo-sulfur compounds, chalcones, etc. Previously, it has been envisaged that mTOR-STAT3 signaling was targeted by PEITC, which eventually led to cytotoxic effects on ovarian cancer cells [87]. Furthermore, PEITC-treated SKOV-3, OVCAR-3, and TOV-21G cells showed a significant decrement in the cellular proliferation in a dose-dependent manner following 24 h of exposure, and the IC50 for SKOV-3, OVCAR-3, and TOV-21G cells were found to be 15 µmol, 20 µmol, and 05 µmol, respectively [88]. PEITC treatment reduced the growth of SKOV-3, OVCAR-3, and NUTU-19 cells in a dose-dependent manner with IC50 values around 27.7 µmol, 23.2 µmol, and 25.1 µmol for SKOV-3, OVCAR-3, and NUTU-19 cells, respectively [89]. Furthermore, PEITC significantly inhibited migration and invasion properties of ovarian cancer cells (SKOV-3 and HO8910) and suppressed metastatic properties of epithelial ovarian cancer in a dose-dependent manner [87].
It is widely acknowledged that in the course of metastasis, metastatic cells detach from the primary tumors, enter the blood circulation by invading through stromal tissues, and thereby form metastatic colonies by invading the target organ. Of note, metastasis is one of the major hallmarks of cancer cells, in which numerous signaling molecules contribute to the invasion and migration of tumor cells. Invasion of a cancer cell is promoted by MMPs, zinc-dependent endopeptidases which disassemble the extracellular matrix (ECM). Accumulating evidence has shown that increased activities of MMPs (MMP2, MMP7, and MMP9) play an important role in cell proliferation, survival, invasion, and angiogenesis [90][91]. Interestingly, evidence has shown that ITCs regulate various signal transduction pathways and considerably inhibit the expression/activity of MMPs [92][93][94].
The aforementioned data explicitly highlight the importance of ITCs in the modulation of female-specific cancer proliferation, migration, and invasion-related signal transduction pathways through various intricate mechanisms.

2.2. Impacts of Isothiocyanates on Modulation of Cell Cycle

As a matter of fact, the eukaryotic cell cycle is a tightly regulated process in which a cell undergoes a series of coordinated events, including cell growth, DNA synthesis, and division; perhaps the cell cycle is preliminarily divided into G1, G2, S, and M-phase, and each phase is characterized by their respective cyclins and cyclin-dependent kinases (CDKs). Basically, cyclin D-CDK4/6, cyclin E-CDK2, cyclin A-CDK2, and cyclin B-CDK1 are restricted to G1 phase, G1-S transition, S-phase, G2-phase, and M-phase, respectively. Furthermore, cell cycle progression and arrest are both controlled by various cell cycle regulators. Intriguingly, in the last few decades, various phytochemicals have been demonstrated to block cell cycle progression through various intricate mechanisms, and in fact, lately, these phytochemicals have played an interesting role in controlling cancer.

2.2.1. Impacts of SFN on Modulation of Cell Cycle

It has been envisaged that SFN treatment effectively hampered cell cycle progression in MCF-7 and MDA-MB-231 cells seemingly through the down-regulation of cyclin A, cyclin B, and CDC2; however, at the same time, a significant increment was observed in the expression of p21 and p27, which are the key cell cycle regulators [38]. Furthermore, SFN treatment effectively inhibited cell growth, induced a G2 m cell cycle block, and increased expression of cyclin B1 in MDA-MB-231, MDA-MB-468, MCF-7, and T47D cells [39]. Collectively, the study highlighted that SFN inhibited cell growth, activated apoptosis, inhibited HDAC activity, and decreased the expression of key proteins involved in breast cancer proliferation [39]. Furthermore, SFN treatment of MDA-MB-231, MCF-7, and SKBR-3 cells increased the percentage of cells in G0/G1, while the compound reduced the percentage of cells in S and G2/M. The mechanism of action of SFN was revealed to hamper the cell cycle progression by elevating the expression of cell cycle regulator proteins such as p53, p21, and p27 [41]. SFN-induced cell cycle progression inhibition was linked with reduced Akt signaling, global DNA hypomethylation, and genomic instability [41]. Additionally, SFN reduced the percentage of cells in the G1 and S phases while elevating the percentage of cells in G2/M progression in MCF-7 cells; however, the study did not indicate the mode of action of SFN to block cell cycle [45].
Furthermore, SFN-mediated cytotoxic effects on HeLa, Cx, and CxWJ were seemingly envisaged to the modulation of cyclin B1 and GADD45β, thereby leading to G2/M cell cycle arrest [50]. SFN treatment also induced cell cycle arrest by epigenetic modulations of DNMT3b [51]. Furthermore, SFN treatment resulted in a significant decrease in the percentage of cells in the S and G2/M phases of the cell cycle, while there was a significant increment in the percentage of cells in the G1 phase, indicating SFN-induced G1 cell cycle arrest in SKOV-3 and OVCAR-3 cells [58]. Furthermore, another in vitro study displayed that SFN caused cell cycle arrest in a dose- and time-dependent manner seemingly by reducing the expression of cell cycle-related proteins such as cyclin D1, CDK4, and CDK6 in SKOV-3, T3, and C3 ovarian cancer cells [4]. Mechanistic insights revealed that SFN suppressed the expression of Akt, PI3K, and GSK3-β, indicating the involvement of the Akt-PI3K signaling pathway in cancer initiation and progression [4]. SFN exposure significantly increased the percentage of cells in the G2/M phase while it decreased the percentage of cells in the G1 and S phases in a concentration-dependent manner, indicating SFN caused G2/M cell cycle arrest by down-regulation and dissociation of cyclin B1/Cdc2 complex in PA-1 cells [59]. Moreover, SFN-treated MDAH-2774 cells undergo G1 cell cycle arrest, which was clearly evident from the flow cytometry data, wherein the percentage of cells in the G0/G1 phase increased in comparison to the vehicle control, while there was a negligible increment in the percentage of cells in S phase [60]. Overall, there was a 1.5, 1.0, and 1.5 fold decrement in the expression of retinoblastoma (RB), E2F-1, and E2F-2 proteins, respectively, in SFN-exposed MDAH-2774 cells. Additionally, there was a reduction in the expression of CDK4 and CDK6, as revealed by Western blot analysis [60]. Furthermore, SFN-treated OVCAR-3 and A2780 cells undergo cell cycle arrest seemingly due to the altered expression of cell cycle-associated molecules, including cyclin D1, p27, and p53 [57].

2.2.2. Impacts of BITC on Modulation of Cell Cycle

Of note, it has been envisaged that BITC treatment on MCF-7 and MDA-MB-231 cells showed cell cycle arrest, which occurred in response to the down-regulation of important cell cycle regulators such as cyclin B1, CDK1, and Cdc25C [64]. Amongst the various plausible reasons, BITC-mediated cytotoxicity on cervical cancer cells may be due to the perturbation in the cell cycle; interestingly, accumulation of cells in the G2 and M phase was observed in a dose- and time-dependent manner in both cell lines (HeLa and MRC-5) following treatment with BITC, which may plausibly be attributed to the inhibition of Aurora A, polo-like kinase (PLK1) but not Aurora B activity thereof [68]. Interestingly, BITC treatment for ovarian cancer cells led to the perturbation in the cell cycle progression, which increased the percentage of cells in the G2 and M phase; the mechanism of action behind the activity of BITC to cause G2/M cell cycle arrest was possibly due to the decreased Akt signaling [69].

2.2.3. Impacts of PEITC on Modulation of Cell Cycle

As a matter of fact, heat shock proteins (HSPs) augment cell cycle progression through the increased activity of NF-κB; therefore, it has been envisaged that suppression of these HSPs may be a promising target for the development of cancer drugs. To this end, PEITC treatment significantly down-regulated different HSPs, including Hsp27, Hsp70, and Hsp90, which led to the cell cycle arrest at the G2/M phase, while PEITC decreased the percentage of cells in the G0/G1 and S phases, which ultimately led to reduced NF-κB activity in MDA-MB-231 and MCF-7 cells [72]. Furthermore, it has been reported that PEITC promoted the down-regulation of cyclin B1, CDK1, Cdc25C, and PLK-1 and increased the up-regulation of p53 and p21 in treated MDA-MB-231 and MCF-7 cells [73]. Research has also shown that PEITC treatment in MDA-MB-231 and MCF-7 cells resulted in the increment in the percentage of cells in G1 and G2/M, while a significant reduction in the percentage of cells in the S phase was observed in a dose- and time-dependent manner [74]. Another study showed that PEITC altered the expression of p57 in breast cancer cells, which is an inhibitor of cyclin D and cyclin E; thus, p57 contributes to cell cycle arrest at the G1-phase [77].
Collectively, the above collation of the literature distinctly highlights the importance of ITCs in the regulation of cell cycle arrest in female-associated cancers.

2.3. Impacts of Isothiocyanates on Apoptosis

It is widely known that apoptosis is an ordered and orchestrated cellular process. Morphological hallmarks of apoptosis include chromatin condensation and nuclear fragmentation, which are accompanied by rounding up of the cells, reduction in cellular volume (pyknosis), retraction of pseudopods, etc. At the later stages of apoptosis, some of the morphological features include membrane blebbing, ultrastructural modification of cytoplasmic organelles, and loss of membrane integrity [95]. It is widely known that conventional apoptosis mainly occurs either through an intrinsic mitochondrial pathway or through the extrinsic death receptor-mediated pathway. The mitochondrial death pathway is regulated by Bcl-2 family members and involves the down-regulation of Bcl-2 and Bcl-xL proteins as well as the up-regulation of pro-apoptotic factors that enhance the participation of several signaling pathways. The Bcl-2/Bax ratio is critical for cytochrome-c expression; a low Bcl-2/Bax ratio triggers the release of cytochrome-c from mitochondria, which activates caspase-3, which in turn activates the PARP cleavage that has been recognized as a hallmark of apoptosis. Poly (ADP-ribose) polymerase is a critical enzyme that is particularly involved in the DNA repair and modulation of chromatin structure. Several investigations have revealed that apoptosis may also be induced by oxidative stress [96][97][98][99]. It is reasonable to argue that an important goal of clinical oncology has been the exploration of therapeutic moieties promoting the effective elimination of cancer cells by apoptosis.

2.3.1. Impacts of SFN on Apoptosis

To this end, interestingly, reports have shown that SFN treatment strongly induces apoptosis seemingly through elevating the expression of c-caspase-3, Bax, and c-PARP and down-regulating the expression of Bcl-2 and Bcl-xL in MCF-7 and MDA-MB-231 cells [38]. Several studies have indicated that apoptosis induction can occur through different mechanisms. DNA fragmentation was observed in SFN-exposed MCF-7 and MDA-MB-231 cells, which occurred in a dose-dependent manner. Particularly, in MDA-MB-231 cells, SFN-mediated apoptosis induction occurred in response to Fas ligand activity, leading to the activation of caspase-3 and caspase-8, and PARP inhibition. However, apoptosis in MDA-MB-468, MCF-7, and T47D cells was mediated through increment in the expression of cytosolic cytochrome-c, down-regulation of Bcl-2, and activation of caspase-3 and caspase-9, attributing to decreased expression of estrogen receptor-α, histone deacetylase, and EGFR [39]. Another study on the cytotoxic potential of SFN showed that apoptosis induction in SFN-treated MCF-7 cells occurs due to the suppression of dynamic instability and reduction in microtubule turnover [45]. Furthermore, SFN-treated HeLa cells showed increased apoptosis induction and reduced level of inflammation, which was seemingly linked with down-regulation of Bcl-2 and decreased signaling of IL-1β and COX-2, as also discussed above [50].
Furthermore, apoptosis induction in SFN-treated cervical cancer cells was found to be due to the decreased expression of Bcl-2, Bcl-xL, PARP, and β-catenin and enhanced the expression of Bax and caspase-3 [52]. Another study demonstrated that SFN treatment induced apoptosis in SKOV-3, C3, and T3 cells by increasing the expression of c-PARP in a concentration- and time-dependent manner; nevertheless, the authors have not studied other apoptosis-associated proteins such as Bax, Bcl-2, Bcl-xL, cytochrome-c, and intrinsic and extrinsic caspases [4]. Furthermore, SFN-induced apoptosis in MDAH-2774 cells, which was clearly evident from the flow cytometry data, wherein the number of annexin-V-positive and propidium iodide-positive cells increased with increment in the concentration of SFN, indicating accumulation of early and late apoptotic cells. Basically, SFN-induced apoptosis occurred in response to the elevated expression of Bax, caspase-9, and c-PARP, and reduced the expression of Bcl-2 [60]. SFN was very effective in inducing apoptosis in OVCAR-3 and A2780 cells seemingly by down-regulating Bcl-2 and Bcl-xL, along with the increment in the expression of Bax, caspase-3, and cytosolic cytochrome-c, and there was a significant inhibition of Akt and NF-κB proteins thereof [57].

2.3.2. Impacts of BITC on Apoptosis

BITC-exposed MCF-7 and MDA-MB-231 cells showed considerable apoptotic induction, which was plausibly mediated by ROS generation through inhibition of complex III of the mitochondrial respiratory chain. These events eventually further potentiated Bax and caspase-3 overexpression and down-regulated catalase and superoxide dismutase. Moreover, BITC treatment induced apoptosis in MCF-7 and MDA-MB-231 cells seemingly by up-regulating Bax and Bak along with attenuation of Bcl-2 and Bcl-xL expression [64]. BITC treatment resulted in apoptosis induction in ovarian cancer cells as well. Interestingly, BITC inhibited Bcl-2 expression and up-regulated the expression of caspase-3, caspase-8, c-PARP, and Bax, seemingly via activation of JNK1/2/p38 and inhibition of ERK1/2 and Akt signaling in ovarian cancer cells [100]. Furthermore, BITC-exposed ovarian cancer cells showed significant apoptosis induction in a dose-dependent manner, which occurred in response to the DNA fragmentation and mitochondrial membrane depolarization, which was linked with the reduced expression of Akt protein [69].

2.3.3. Impacts of PEITC on Apoptosis

PEITC exposure to MDA-MB-231 and MCF-7 cells significantly induced apoptosis, which resulted in decreased cell viability. The mechanistic insights into the mode of action of PEITC responsible for apoptosis induction in breast cancer cells were elucidated thereof. It was found that PEITC decreased the expression of Bcl-2 and triggered an increase in the expression of proapoptotic proteins such as Bax, caspase-3, caspase-9, and caspase-8, while at the same time, PEITC reduced the expression of mitochondrial cytochrome-c and promoted the expression of cytosolic cytochrome-c [73]. Furthermore, another study investigated the effects of PEITC on human breast cancer cells (MDA-MB-231 and MCF-7). Interestingly, it was found that PEITC readily induced apoptosis in MDA-MB-231 cells (as indicated by ready activation of caspases-9 and 3, and decreased expression of Bax); nevertheless, MCF-7 cells were relatively resistant to the apoptotic effects of PEITC. It was envisaged that the relative resistance of MCF-7 cells was seemingly associated with high basal expression of NRF2, a transcription factor that coordinates cellular protective responses to oxidants and electrophiles, and raised intracellular levels of GSH. Thus, differences in the basal expression of NRF2 and resultant changes in GSH levels seem to be an important determinant of sensitivity to PEITC-induced apoptosis [74]. Furthermore, another interesting study demonstrated that PEITC-induced apoptosis in breast cancer cells was independent of the p53 up-regulated modulator of apoptosis (PUMA), but the apoptosis induction occurred in response to the B-cell lymphoma 2 interacting mediator of cell death (Bim), Bax, Bak, and caspase-3 activation [78]. Moreover, DNA fragmentation, down-regulation of Bcl-2 and XIAP, Smac translocation, and release of cytochrome-c into the cytosol with concomitant PARP cleavage and decreased expression of procaspase-7 and procaspase-9 significantly contributed to PEITC-induced apoptosis in MCF-7 cells, indicating the involvement of the mitochondrial pathway [101].
PEITC exposure to cervical cancer cells resulted in the activation of death receptors 4 and 5 (DR4, DR5), which further led to apoptosis induction in these treated cells [82]. Moreover, the inhibitory effects of PEITC were due to the activation of caspase-3 and -8, which may be in response to the down-regulation of ERK and MEK pathways [82]. Accumulating evidence has highlighted the impact of PEITC on the up-regulation of apoptosis-associated proteins in HeLa cells.
PEITC-mediated cytotoxicity in CaSki and HeLa cells was triggered in response to the apoptosis induction through intracellular and mitochondrial ROS generation, which led to nuclear fragmentation and caspase-3 activation thereof [85]. Furthermore, PEITC-mediated cytotoxicity was due to a 4–6-, 2–5-, and 2–10-fold increase in apoptosis induction in OVCAR-3, SKOV-3, and TOV-21G cells, respectively, which is achieved through promoting the expression of c-caspase-3 and c-PARP [88]. PEITC treatment resulted in a reduction in phosphorylation of EGFR and Akt, leading to decreased EGFR and Akt activities in OVCAR-3, SKOV-3, and TOV-21G cells, which are positively correlated with the activation of caspase-3 and PARP cleavage [88]. Further investigations on the mode of action of PEITC revealed that PEITC targets the key signaling pathways of ovarian cancer because PEITC inhibited TGF-dependent activation of EGFR-Akt, and there was significant inhibition of Rictor, Raptor, mTORC1, and mTORC2 thereof [88]. The morphological analysis of PEITC-treated SKOV-3, OVCAR-3, and NUTU-19 cells revealed that PEITC induced morphological changes such as rounding, detachment, and floating cells which are the major hallmarks of apoptosis induction [89]. Furthermore, PEITC-mediated apoptosis induction was validated by increased activation of caspase-3, caspase-8, and caspase-9, and enhanced expression of Bax and c- PARP, while a significant reduction was noted in the expression of Bcl-2 in PEITC-exposed ovarian cancer cells [89]. Further investigations on the molecular mechanism of PEITC revealed that apoptosis induction in ovarian cancer cells occurred seemingly through increased phosphorylation of JNK1/2 and p38 and reduced phosphorylation of ERK1/2, Akt, and c-Myc, indicating PEITC targets JNK/p38 and ERK/Akt signaling pathways [89]. PEITC was cytotoxic to ovarian cancer cell lines, including OVCAR-3, SKOV-3, PA-1, CAOV3, and A2780, and PEITC promoted mitochondrial ROS generation, which thereby inhibited complex III of the electron transport chain leading to significant cell death in these ovarian cancer cells [102]. Another study demonstrated that PEITC induced ROS accumulation to activate apoptotic cascade via unfolded protein response (UPR) in ovarian cancer cells. Additionally, PEITC-mediated apoptosis occurred through up-regulating CHOP/GADD153 and Bip/GRP78 with concomitant activation of PERK and IRE1 in SKOV-3 and PERK and ATF-6 in PA-1 ovarian cancer cells. PEITC treatment caused excessive ROS production in order to inactivate redox-sensitive molecules, induce mitochondrial damage, and increase apoptosis induction which cumulatively showed the selective killing of ovarian cancer cells [103].
These scientific observations indicate that ITCs have significant potential to induce apoptosis in breast, cervical, and ovarian cancer attributed to the modulation of several molecular mediators involved in apoptotic responses.

2.4. Impacts of Isothiocyanates on Modulation of Autophagy

Autophagy is an evolutionarily conserved intracellular recycling system and cellular self-degradation process that maintains metabolism and homeostasis [104]. In cancer biology, autophagy plays dual roles in tumor promotion and suppression and contributes to cancer-cell development and proliferation [105][106]. It has been envisaged that autophagy is an attractive target for cancer therapeutics, and researchers have been exploiting the use of autophagy modulators as adjuvant therapy [107][108]. Interestingly, accumulating evidence has shown that isothiocyanates (SFN, BITC, and PEITC) trigger autophagic cell death seemingly through alteration of various signaling molecules, including mTOR, microtubule-associated protein 1 light chain 3 (LC3), beclin-1, p68, Akt, AMPK, PTEN, FOX1, etc. [109].

2.4.1. Impacts of SFN on Modulation of Autophagy

An in vitro study showed that SFN induced considerable autophagy in MDA-MB-231, MCF-7, SKBR-3, and MDA-MB-468 cells. Interestingly, transmission electron microscopy (TEM) and fluorescence microscopic analysis showed vacuole formation and the presence of GFP-tagged LC3 protein in the vacuoles in the SFN-treated group. Furthermore, mTOR is a negative regulator of autophagy, and SFN decreased the phosphorylation level of mTOR, leading to autophagy induction in triple-negative breast cancer cells (TNBCs) [36]. Another report has also envisaged that SFN-treated breast cancer cells showed autophagy induction, asserted by the presence of membranous vacuoles, autophagosomes and autolysosomes, and accumulated acidic vasicular organelles [38]. Furthermore, SFN exposure to breast cancer cells reduced ATP and lactate levels, which may be judged by AMPK activation, while SFN decreased the level of phospho-Akt without affecting glucose transporter 1 (GLUT1), hexokinase 2, lactate dehydrogenase A (LDHA), and pyruvate kinase isoform 2 (PKM2). This reduced energy stress in response to a decreased level of ATP, and AMPK activation promoted cytotoxic and cytostatic autophagy in the breast cancer cells [40]. Interestingly, SFN exposure to different breast cancer cells resulted in significant autophagy induction by increasing expression of LC3-I, LC3-II, and beclin-1, while a decline in the level of P62 was observed in treated cells [110]. Another preclinical study showed that SFN has a significant ability to induce autophagy in breast cancer cells (MDA-MB-231, BT549, and MDA-MB-468 cells) by targeting down-regulation of HDAC6 which increased translocation and acetylation of PTEN. Furthermore, mechanistic insights revealed SFN-mediated elevation in beclin 1 and LC3-II expression and down-regulated p62 expression levels in TNBC cells [110].

2.4.2. Impacts of BITC on Modulation of Autophagy

TEM analysis revealed that BITC treatment resulted in the formation of double-membrane vacuoles resembling autophagosomes, acidic vasicular organelles, and cleavage of microtubule-associated protein 1 light chain into LC3-II in BITC-treated breast cancer cells [64]. Furthermore, breast cancer cells pre-treatment with autophagy inhibitors (3-methyl adenine and bafilomycin A1) resulted in partial but statistically significant attenuation of BITC-mediated growth inhibition [64]. Furthermore, FOX1-dependent autophagy was induced in human breast cancer through BITC administration [109]. Interestingly, autophagy induction and attenuated growth of MCF-7 cells were due to the cleavage of LC3, diminished activity of p68, and inhibition of mTOR activation [109].

2.4.3. Impacts of PEITC on Modulation of Autophagy

Reports have shown that PEITC induces autophagy in various cancers [111][112]. It has been highlighted that PEITC induces autophagic cell death in prostate cancer cells, and it has been argued that PEITC-induced autophagy was plausibly regulated by Atg5 [112]. Furthermore, PEITC-mediated autophagy induction has also been reported in transgenic mice models of prostate cancer [113].
Albeit, there is information highlighting the impacts of PEITC on the modulation of autophagy in various cancers; nevertheless, as of now and to the best of researchers' knowledge, reports highlighting the impacts of PEITC on the modulation of autophagy in female-specific cancer is rare.
Collectively, all these data envisage the importance of ITCs in the modulation of autophagic responses in female-specific cancer.

2.5. Impacts of Isothiocyanates on Cancer Stem Cells (CSCs)

Of note, CSCs are the subpopulations of tumor cells that actively participate in tumor initiation and progression. The key signaling pathway that acts as a major regulator for CSCs is the PI3K/Akt/mTOR signaling pathway [114]. It has been highlighted that various molecular mediators, including aldehyde dehydrogenase (ALDH), CD44, CD24, Nanog, Notch, c-Myc, Oct-4, Sox-2, KLF4, Slug, and Wnt/β-catenin signaling considerably contribute to CSC proliferation and metastasis. It has been envisaged that CSC formation occurs in response to chemotherapy, resulting in the failure of cancer therapy. Therefore, screening phytocompounds with the potential to limit the formation and spread of CSCs has been in demand. Thereby, various ITCs have been analyzed to inhibit the growth and proliferation of CSCs.

2.5.1. Impacts of SFN on CSCs

Interestingly, it has been highlighted that SFN-treated MCF-7 and SUM159 cells showed reduced primary sphere formation, and there was a 65% and 80% reduction in the ALDH-positive cell population in SUM159 at 1 and 5 µmol/L concentration of SFN, respectively. Furthermore, SFN-treated animals also confirmed a decline in the number of ALDH-positive cells in breast tumors [49]. Mechanistic insights revealed that SFN-induced cytotoxic and antitumor effects were plausibly due to the down-regulation of the Wnt/β-catenin self-renewal pathway [49]. This down-regulation of Wnt/β-catenin in SFN-treated MCF-7 and SUM159 cells also led to a reduction in the cyclin D1 expression, which is a downstream protein of this signaling pathway, as highlighted in the above sections. SFN-treated TNBCs (MDA-MB-231-Luc-D3H1 and JygMC(A)GFP/Luc) showed proliferation inhibition, suppression of self-renewal of breast CSCs, and a reduced number and diameter of primary and tertiary tumor spheres, while SFN-treated CD49f+/CD24−/CD44+ breast CSCs showed a significant reduction in the number of secondary tumor spheres as well [115]. Interestingly, the study also highlighted that the tumor sphere forming-presumptive CSCs were more sensitive to SFN treatment than the unsorted bulk of TNBC cells. In comparison to the saline-treated animal group, SFN-pre-treated animals showed reduced gene expression of CSC markers, including Nanog, forkhead box D3 (FOXD3), Wnt3, ALDH1A1, and Notch4 during primary tumor growth. SFN (stabilized in alpha-cyclodextrin complex) treatment also inhibited breast CSC activity in primary and metastatic estrogen receptor-positive breast cancer patient-derived samples, seemingly by reducing mammosphere formation efficiency (MFE) and ALDH activity [116]. Importantly, the molecular mechanism responsible for the anti-bCSC action of SFN was revealed as a reduction in pSTAT3 levels and decrement in the number of ALDH-positive bCSCs and tumorigenicity [116].

2.5.2. Impacts of BITC on CSCs

In vitro and in vivo studies have conferred the chemopreventive role of BITC, as it also inhibited the self-renewal of breast CSCs through reducing expression of Ron, N-cadherin, and vimentin along with E-cadherin overexpression [117]. An emerging paradigm suggests that BITC can also suppress CSC properties in different cancers by targeting various CSC-related marker proteins. Notably, B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1) and Notch4 serve as regulators of bCSC self-renewal and maintenance. BITC-treated MCF-7, SUM159, MDA-MB-231, MDA-MB-361, and MDA-MB-231 xenografts showed significant suppression of Bmi-1 [118]. Furthermore, BITC-mediated reduction in the ALDH1 activity was linked with the Bmi-1 expression in MDA-MB-231 and SUM159 cells, and over-expression of Bmi-1 in MCF-7 cells significantly attenuated BITC-dependent mammosphere formation [118]. BITC caused significant activation of Notch4, which indicated BITC possesses anti-breast CSC potential [118]. Another in vitro study demonstrated that BITC-exposed human breast cancer cells also increased the level of Notch1, Notch2, and Notch4, and the Notch activation was accompanied by induction of secretase complex component Nicastrin [70]. One of the interesting preclinical studies highlighted the role of BITC in targeting kruppel-like factor (KLF-4)-p21CIP1axis, which is generally implicated to be involved in the maintenance of bCSCs [119]. Moreover, BITC-treated MDA-MB-231, MCF-7, and SUM159 cells resulted in the induction of KLF-4 in a dose-dependent manner, and BITC also promoted KLF-4 mRNA expression [119]. KLF-4 knockdown augmented BITC-derived suppression of bCSCs, leading to a reduction in the ALDH-positive bCSC population both in MCF-7 and SUM159 cells. Furthermore, KLF-4 knockdown and BITC treatment are more effective in suppressing mammosphere formation when compared to either KLF-4 knockdown or BITC treatment alone, and KLF-4 knockdown resulted in the suppression of p211 in both MCF-7 and SUM159 cells, indicating bCSCs inhibition by BITC treatment is partially attenuated by the induction of KLF-4 and p21 [119].

2.5.3. Impacts of PEITC on CSCs

PEITC treatment to chemo and radio-resistant breast cancer cells (MDA-MB-231/IR) resulted in intensive ROS generation, decreased metadherin (MTDH) expression, and reduced breast CSCs. Furthermore, the MTDH knockdown significantly promoted a reduction in ALDH activity and inhibition of CSC markers such as β-catenin, CD44, and Slug [120]. Furthermore, PEITC treatment resulted in the inhibition of the viability of ALDH-positive cells, decreased self-renewal ability, and inhibition of sphere formation efficiency in ovarian cancer (SKOV-3) and breast cancer cells (BT474, SKBR3, and HCC1954). Further investigations at the molecular level revealed that PEITC down-regulated phosphorylated HER2 monomer and reduced expression of Notch1 and Hes1 mRNA [121]. PEITC significantly attenuated the expression of ALDH1, resulting in the decreased cell viability of ALDH1-positive HeLa CSCs by increasing early apoptosis induction through the production of ROS and inhibition of Sp1 and promoter region of MDR1 (P-Gp) in PEITC-treated HeLa CSCs [122]. In comparison to MDA-MB-231 cells, radioresistant MDA-MB-231/IR cells showed higher expression of the CSC-associated marker proteins, and PEITC exposure to these cells suppressed cancer cell stemness through the down-regulation of CSC markers such as CD44, oct3/4, and Slug, and the down-regulation of metadherin protein at the post-transcriptional level [120].
In summation, it is reasonable to argue that the formation and spread of CSCs are considerably halted by ITCs, including SFN, BITC, and PEITC.

This entry is adapted from the peer-reviewed paper 10.3390/cancers15082390

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