Page 27 - GPD-2-1

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

inhibition [184] . Furthermore, NAC treatment can inhibit suggested that the treatment with NaHS promotes
radiotherapy-induced premature ovarian failure through apoptotic activities through the activation of p38 and p53
the suppression of nicotinamide adenine dinucleotide cascades in C6 cells [193] . Similarly, in colon cancer, NaHS
phosphate oxidase 4 (NOX4)/MAPK/p53 pathway and the treatment promotes cancer progression and metastasis
promotion of VEGF, thus conserving ovarian function [185] . by upregulating the expressions of SIRT-1, p-AKT, and
In addition, NAC can reduce oxidative injury by increasing p-ERK as well as downregulating p21 [194] . In a recent study,
GSH peroxidase activity and decreasing the expression of NaHS reduced cell proliferation in CRC, but it did not
nicotinamide adenine dinucleotide phosphate oxidase induce apoptosis by upregulating Ca levels through the
2+
subunits (p22 and NOX4). It has also been demonstrated activation of transient receptor potential cation channel
that NAC treatment can effectively attenuate cell subfamily V member 1; the effect was only observed in
invasiveness and proliferation in pancreatic cancer by metastatic cells but not in normal cells [195] .
regulating the cell cycle [186] . The combination of NAC In multiple myeloma and oral squamous cell carcinoma,
with anticancer drugs, such as bromelain and curcumin, NaHS exhibits pro-cancer effects by promoting the
results in potent anticancer activities that are associated phosphorylation of AKT and ERK1/2 cascades [196] . Moreover,
with attenuating migration markers such as MMP-2 and -9 it promotes cancer metastasis through the activation of HSP-
as well as suppressing ROS-induced activation of ERK/ 90 and JAK2/STAT-3 in esophageal carcinoma EC109 cells;
NF-κB [187] .
NF-κB, STAT-3/COX-2, and HIF-α/adenosine triphosphate-
In HCC, treatment with NAC can restore sensitive potassium channel activation in HCC; and the
intracellular GSH levels and IL-2-induced cytotoxicity of upregulation of MMP-2/-9 in bladder cancer EJ cells [197] .
mononucleated cells [188] . NAC reduces liver damage and Alternatively, in lung cancer, treatment with NaHS alleviates
the incidence of post-embolization syndrome following carcinogenic activities, including EMT, through TGF-β1/
transarterial chemoembolization in HCC patients [189] . In Smad2/Smad3 suppression and the activation of caspase-3,
lung cancer, NAC adducts are significantly lowered, and its p21, and p53 cascades [198,199] .
administration reduces the oxidative stress and senescence NaHS also inhibits the proliferation of melanoma
caused by the inactivation of transcription factor JunD, cells by blocking PI3K/AKT/mTOR activation and breast
in addition to lung emphysema; however, it concurrently cancer cells by inducing G0/G1 arrest and p-p38 MAPK
promotes the progression of cancer [190] . Briefly, these data inhibition. In neuroblastoma, treatment with NaHS
suggest that NAC has inhibitory properties on different suppresses adenylyl cyclase and γ-secretase, reduces
types of cancers. Its combination with other drugs may intracellular cyclic adenosine monophosphate levels and
further enhance/attenuate the effect, depending on the dynamin-like protein expression, and increases ERK
drug’s mode of action. Besides, the cotreatment of NAC phosphorylation [199,200] . These data imply that H S has a role
with for drugs that initially work by facilitating ROS in cancer progression; however, the potential of NaHS for
2
generation may not be a good option due to the antioxidant cancer treatment is relatively insignificant.
properties of nicotinamide adenine dinucleotide (NAD).
2.2.2. Sodium sulfide (Na S)
2.2. Native compound 2
Na S is another fast-releasing H S-donating compound
2.2.1. Sodium hydrosulfide (NaHS) that is associated with cancer therapeutics. In CRC
2
2
NaHS is a fast-releasing H S compound and one of the patients, Na S treatment in human mesenteric arteries
2
2
most common donors in H S-related research. Being a results in the relaxation of vessels by targeting potassium
2
fast-releasing donor, it produces enormous amounts of ion (K ) channels [201] . The compound has been reported
+
H S in a remarkably short period of time followed by a to selectively kill glioblastoma T98G and U87 cells, while
2
subsequent decline in production. Depending on the dose showing no effect in cerebral microvascular endothelial cells
administered and the type of cancer and cell, the drug is (D3), through a mechanism that involves the elevation of
known to induce dual effects; thus, there are numerous ROS levels and the suppression of mitochondria activities,
conflicting reports. The compound also regulates resulting in DNA damage and subsequent cell death [202] .
cellular processes, resulting in the modulation of tumor In addition, Na S treatment also sensitizes glioblastoma
2
growth and sensitivity to drugs [191] . In a glioblastoma cells to radiotherapy [203] . In an earlier study, the anticancer
model, treatment with NaHS facilitated tumor growth effect caused by the inhibition of CBS in ovarian cancer
in the animal model by upregulating HIF-α expression was found to be reversible with low doses of Na S [204] .
2
and in C6 cells by activating the p38MAPK/ERK1/2/ Despite the fact that there are only a number of studies on
COX-2 signaling axis [192] . However, another study has Na S, evidence has indicated that Na S has protective and
2
2
Volume 2 Issue 1 (2023) 12 https://doi.org/10.36922/gpd.v2i1.164