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

robust anticancer effects. However, its inability to imitate suggest that GYY2137 could serve as a potential anticancer
the physiological production of H S affects its applicability. drug. However, further research is needed to investigate
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the mechanism of action, cellular marker, and signaling
2.2.3. Other metal sulfides pathways involved.
Apart from Na S, sulfides of other metals, such as calcium
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and copper, also have anticancer properties, as witnessed 2.3.2. 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione
in experimental settings. Although there are no existing (ADT-OH)
studies on individual drug administration containing ADT-OH is an artificial H S donor with significant
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the aforementioned metal sulfides in cancer; their chemoprotective effects against cancer cells. It is an
nanoparticle formulations have been well-documented. extraction from amphiphilic block copolymers containing
Calcium sulfate (CaS) nanoparticles are known to trigger an ester bond linking ADT-OH using isoleucine and glycine
cell cycle arrest and induce apoptosis in lung cancer cells, linkers [213] . In a recent study, treating melanoma cells with
but no significant effect has been reported in normal ADT-OH have been shown to inhibit the progression
cells [205] . Similarly, copper sulfate (CuS) nanoparticles have of cancer by downregulating XIAP and Bcl-2 as well as
been reported to possess the ability to target tumor cells stabilizing Fas-associated protein with death domain and
and penetrate their nucleus by modifying surface peptides IκB-α, resulting in NF-κB inactivation [214] . Furthermore,
RGD and TAT [206] . In a study, the cotreatment of CuS connecting ADT-OH with hyaluronic acid forms another
nanoparticles with 980 nm near-infrared laser irradiation novel H S donor (HA-ADT), which can produce more H S
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causes cell death by increasing the temperature of the and induce more anticancer effects in breast cancer than
nucleus and destroying the genetic materials. In cervical commonly used donors, such as NaHS and GYY4137 [215] .
cancer cells, CuS nanoparticles have been shown to induce This effect is associated with the deactivation of PI3K/
a concentration-dependent photothermal destruction AKT/mTOR and RAS/RAF/MEK/ERK pathways. The
with low cytotoxicity [207] . The evidence suggests that above evidence supports the use of H S in the treatment of
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metal sulfides are useful as H S donors and have a role in cancer and suggests that newly synthetic donors with high
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cancer suppression; however, further research is needed to efficiency could be the key.
illuminate the mechanisms involved and side effects.
2.3.3. S-propargyl-cysteine (SPRC)
2.3. De novo design
SPRC, also known as ZYZ-802, is a structural analog of
2.3.1. Morpholin-4-ium 4 methoxyphenyl(morpholino) S-acetyl cysteine and a crucial substrate for CSE, thus
phosphinodithioate (GYY4137) making it an endogenous H S donor. Like other H S donors,
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GYY4137 is the most common synthetic slow-releasing SPRC regulates cellular activities, including inflammation,
H S donor in research. It is soluble in water and exhibits apoptosis, and oxidative stress. In a mice model of gastric
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a strong anticancer effect in both cellular and animal cancer implants, treatment with SPRC significantly
models. In various cellular models of cancer, including reduced tumor weight and volume by promoting pro-
prostate, cervical, lung, breast, and ovarian cancer, apoptotic activities in cancer tissues through the elevation
treatment with GYY4137 can effectively promote pro- of Bax expression, cell cycle arrest at G1/S phase, and the
apoptotic activities by increasing lactate production, activation of p53 pathway [216] . The anticancer effects of
reducing intracellular pH levels, and facilitating G2/M SPRC can be reversed with peginterferon alfa-2a (PAG)
arrest [208] . In CRC, treatment with GYY4137 promotes cell treatment. Likewise, in pancreatic cancer, treatment with
cycle arrest, apoptosis, and necrosis [209] . In addition, drug SPRC causes the inhibition of cell viability and proliferation
causes intracellular acidification in both ovarian and CRC by triggering G2/M arrest and apoptosis through the
cancer, due to uncoupling of sodium-calcium exchanger upregulation of p53 and a reduction in JNK degradation
1 and sodium-hydrogen exchanger1 channels [210] . through phosphorylation [217] . From the information above,
Treating colon cancer cells HCT116 with GYY4137 SPRC has shown potential in cancer treatment; however,
also increase LDHA activity and induce concentration- a dearth of research has limited its applicability in clinical
dependent cell death by inactivating cGMP/VASP, AKT, settings.
and p44/42 MAPK (ERK1/2) pathways [187] . Moreover, in
HCC, GYY4137 upregulates caspases and blocks STAT-3 2.3.4. (10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)
phenoxy) decyl) triphenylphosphonium bromide
activation, thereby inducing G1/S arrest and cell death [211] .
In a recent study, GYY4137 has also been shown to protect (AP39)
neuroblastoma cells against lipopolysaccharide-induced AP39 is a compound that targets mitochondria through
elevation of inflammatory activities [212] . The above data triphenylphosphonium moiety and releases H S inside the
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Volume 2 Issue 1 (2023) 13 https://doi.org/10.36922/gpd.v2i1.164