Page 22 - GPD-2-1

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

thioredoxin, increases ROS generation and Bak expression, thyroid carcinoma, it has been found that the induction of
stimulates activator protein (AP)-1 and apoptosis signal- apoptosis is associated with the activation of ERK, JNK,
regulating kinase (ASK)1-JNK-Bim signaling axis, and MAPK pathways, G2/M arrest through ATM and
and deactivates transforming growth factor (TGF)-β1, H2AX phosphorylation, and a positive feedback loop
Wnt/β-catenin, NF-κB, ERK/MAPK, AKT, and Notch due to a rise in H S and CSE levels, resulting in NF-κB
2
pathways . In mice models, the combination of DATS and hyperactivation . It has been shown that treating colon
[95]
[84]
doxorubicin has been reported to induce multi-signaling cancer cells with DATS can significantly promote cell
targeted apoptosis, inhibit Notch and NF-κB pathways, death and reduce migration activities by inhibiting focal
and activate the p53 apoptotic axis . Similarly, treatment adhesion kinase (FAK), Src, and Ras, facilitating G1/S
[85]
with DATS in bladder cancer markedly suppresses EMT. arrest by oxidating β-tubulin, ROS production, and
DATS also elevates apoptotic activities in a caspase- mitochondria-mediated apoptosis .
[96]
dependent manner through the inhibition of PI3K/AKT The elevation of Ca levels, the generation of ROS,
2+
and the activation of JNK pathway .
[86]
the downregulation of antiapoptotic proteins, integrins,
Recent studies have reported an increase in apoptosis and FAK, and the activation of caspases and p53 pathway
and a decrease in EMT in bladder carcinoma cells following have been observed in skin cancer cells following DATS
DATS treatment. G2/M arrest, NF-κ2 inactivation, ATM- treatment . Likewise, DATS improves the anticancer
[97]
mediated CHK2/Cdc25C/Cdc2 stimulation, and ERK1/2, effects of cisplatin in ovarian cancer cells (SKOV-3) . In
[98]
JNK, and p38 phosphorylation were observed . In gastric leukemia, DATS treatment suppresses cancer progression
[87]
cancer, DATS treatment exerts pro-apoptotic properties by triggering G0/G1 arrest and caspase activation, the
by inducing mitotic arrest through ROS-dependent disruption of mitochondria potential due to high ROS
activation of AMP-activated protein kinase (AMPK) levels , and the dimerization of heat shock protein
[99]
pathway, regulating apoptotic markers , and reducing (HSP)-27. In brain cancer, DATS reduces migration and
[88]
ROS, sulfiredoxin, and malondialdehyde (MDA) levels. proliferation activities by suppressing Wnt/β-catenin,
DATS also sensitizes gastric cancer cells to docetaxel and mTOR, EGFR, C-MYC, active Bcl-2, and HDAC activity,
cisplatin by elevating the levels of metallothionein 2A, and increasing histone acetylation and p21/p53 levels [100] .
which leads to NF-κB pathway inhibition, and inhibiting
Nrf2/AKT as well as activating p38MAPK/JNK signaling In pancreatic cancer, lymphoma, and nasopharyngeal
cascades, respectively . carcinoma, DATS induces apoptosis through p53 elevation,
[89]
TRAF-6 degradation and NF-κa inactivation, as well as
Besides that, in the treatment of osteosarcoma with DATS, caspase-8 and MAPK pathway activation, respectively [101] .
the compound also suppresses tumor growth by targeting Collectively, the above data confirms the potential of DATS
G0/G1 through decreasing cyclin D1 and upregulating in cancer treatment by targeting numerous vital signaling
p21 and p27 by ROS-mediated PI3K/AKT inhibition . pathways associated with proliferation and migration
[90]
DATS also suppresses P-gp and glucose-regulated protein activities. However, the research on the possible side effects
78, switches microRNA levels, downregulates NF-κB and and mode of action of this drug is still lacking regardless
Notch 1 pathways, as well as upregulates the expression of the possibility. Figure 2 explains the signaling pathways
of Ca -binding protein calreticulin . A recent study has involved in the apoptosis induction effect of DATS
2+
[91]
also reported the downregulation of vimentin and Bcl-2 as exposure.
well as the upregulation of Bax, Bak, and E-cadherin due
to PI3K/AKT/GSK3β inhibition following the treatment of 2.1.6. Sulforaphane (SFN)
osteosarcoma cells with DATS . SFN is a sulfur-rich isothiocyanate (ITC) member
[92]
Otherwise, in the treatment of lung cancer with commonly found in cruciferous vegetables, such as broccoli
DATS, the compound promotes DNA damage and and cabbages. The compound is known to have anticancer
apoptosis through the elevation of caspase-3, -8, -9, Bax, properties. In a study, SFN has been reported to have a potent
and Bak; the attenuation of Bcl-xl and Bcl-2 proteins; as inhibitory effect in bladder cancer cells, which is associated
well as the induction of JNK, p53, and p38 pathways . with the suppression of growth promoters such as survivin,
[93]
DATS can also potentiate its protective effect in lung EGFR, and human epidermal growth factor receptor 2
cancer by suppressing Wnt/β-catenin . Furthermore, (HER2) [102] . Treating bladder cancer cells with SFN also
[94]
its modification with extracellular microparticle carriers upregulates insulin-like growth factor (IGF)-binding
enhances anti-inflammatory and ROS activities by protein-3, caspase-3, cyt c, and cell cycle inhibitor p27,
suppressing S100 calcium-binding protein A8/A9, serum resulting in G0/G1 arrest, as well as induces ROS-dependent
amyloid A, fibronectin, IL-6, and toll-like receptor-4. In mitotic arrest, Nrf-2 activation, HDAC inhibition [103] , NF-κB

Volume 2 Issue 1 (2023) 7 https://doi.org/10.36922/gpd.v2i1.164