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Gene & Protein in Disease Therapeutic opportunities in hydrogen sulfide for cancer research

effects. In breast cancer, AIC induces cell death by activating NF-κF ligand [144] . The reduction of XIAP, FOXQ1, STAT-
both mitochondria-dependent and -independent 3, AKT, TGF-β, and TNF-α expressions and the elevation
pathways [134] . G2/M arrest, ERK activation, and NF-κB of ROS, caspases, FOXO1, and JNK/p38 MAPK activation
inhibition have also been observed in breast cancer cells have been observed in breast cancer cells following BITC
following AIC treatment [135] . However, in a recent study, treatment [145] . In lung cancer, BITC has been shown to
AIC could not potentiate any significant apoptosis and suppress the resistance of cells to gefitinib and promote
its treatment yielded in the upregulation of antiapoptotic autophagy, apoptosis, and ROS generation [146] . It has also
marker Bcl-2 and MTOR gene [136] . The reason behind this been suggested that BITC treatment can induce oral cancer
discrepancy is yet to be determined. Besides, in cervical cell death by mediating G2/M arrest and DNA damage
cancer, oral cancer, lung cancer, and glioma, treatment by elevating pro-apoptotic markers and decreasing
with AIC significantly attenuates Bcl-2/Bax status, antiapoptotic ones [147] . In head-and-neck squamous cell
activates caspases, and promotes S/G2/M arrest, thus carcinoma, BITC can suppress EMT markers such as
potentiating its anticancer effect [137] . In bladder cancer, vimentin and activate pro-apoptotic markers such as
AIC promotes pro-apoptotic activities by facilitating the caspase-3 and poly-ADP ribose polymerase (PARP), thus
activation of JNK, the phosphorylation of Bcl-2, and cell resulting in anticancer activities [148] .
cycle arrest [138] . In a recent study, treatment with AIC Moreover, in HCC, BITC treatment has been reported to
nanoparticles in bladder cancer cells has demonstrated have anti-survival effects due to the reduction of MMPs and
that AIC nanoparticles inhibit cell proliferation more MAPK pathways [149] . In pancreatic cancer, BITC treatment
potently compared to AIC by targeting pro-inflammatory can suppress the expressions of antiapoptotic proteins such
markers, such as IL-6, tumor necrosis factor (TNF)-α, and as XIAP, p-PI3K, p-AKT, p-mTOR, p-FOXO1, p-FOXO3a,
inducible nitric oxide synthase (iNOS) [138,139] . Treatment p-STAT-3, and NF-κB as well as activate MAPK pathways,
with AIC also suppresses EMT events in HCC cells [139] . resulting in increased cellular apoptosis and decreased
Moreover, in CRC, the antimetastatic effects of AIC have angiogenesis [150,151] . Besides, BITC has antiproliferative
been reported to be associated with mitotic arrest, Ca effects when used to treat gastric cancer. These effects are
2+
release, growth arrest and DNA damage inducible protein associated with the inhibition of ERK1/2, Ras, iNOS, and
153 (GADD153) activation, and the suppression of MMP COX-2 as well as the activation of death receptors [152] . The
expression and MAPK pathway [140] . Overall, AIC has above evidence validates the potential of BITC in cancer
shown potential in cancer treatment, although further treatment; however, further investigations are needed to
studies are needed to understand the mechanisms involved understand the mechanisms of action for this donor and
and its clearance mechanism. how H S moiety participates in ROS generation.
2
2.1.9. Benzyl isothiocyanate (BITC) 2.1.10. Phenylethyl isothiocyanate (PEITC)
BITC is another natural H S donor and ITC derivative, PEITC is a slow-releasing H S donor and a member of ITCs.
2
2
which is strongly linked with cytoprotection and anti- The donor works by regulating the cell cycle and oxidative
carcinogenesis. The anticancer effect of BITC has been stress, ultimately causing apoptosis. In oral cancer, PEITC
well-documented in several papers. In bladder cancer, has been reported to suppress the expressions of pro-
BITC has been shown to reduce the incidence of cancer migration markers, such as MMP-2 and -9, and increase
in mice that are treated with the carcinogenic compound the expressions of tissue inhibitor matrix metalloproteinase
N-butyl-N-(4-hydroxybutyl) nitrosamine and in cellular (TIMP)-1 and TIMP-2 by inhibiting several pathways,
models through the upregulation of miR-99a-5p through including MAPK, NF-κB, and EGFR signaling cascades [153] .
ERK/c-Jun/AP-1 activation, which, in turn, downregulates PEITC also induces cell death by activating mitochondria-
the expressions of IGF1R, mTOR, and fibroblast growth apoptotic pathways, death receptors, p21/53, and cell cycle
factor receptor 3 cascades and reduces cell survival [141] . arrest [154] . In glioblastoma, PEITC promotes apoptosis,
BITC treatment also promotes ROS production, G1 cell cycle arrest, and anti-EMT activities through the
arrest, and protective autophagy through mTOR activation of intrinsic and extrinsic pathways, along with
inhibition [142] . In breast cancer, treatment with BITC can the downregulation of MMPs, CDC20, cyclin B1, MCL-1,
effectively suppress pro-survival activities by targeting and XIAP expressions [155] . Similarly, PEITC treatment has
p53/liver kinase B1 (LKB1) and p73/LKB1 cascades and also been shown to inhibit death receptors and activate
overexpressing transcription factor Krüppel-like factor TGFβ/Smad2 signaling pathways in cervical cancer [156] .
4 (KLF4) [143] . In addition, BITC can prevent osteoclast In the treatment of gastric cancer with PEITC, the latter
differentiation in breast cancer cells by inhibiting runt- inhibits the expressions of MMPs, FAK, Ras, growth
related transcription factor 2 and receptor activator of factor receptor-bound protein 2, COX-2, and VEGF

Volume 2 Issue 1 (2023) 10 https://doi.org/10.36922/gpd.v2i1.164