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

2.4.2. NOSH-sulindac (AVT-18A) CSE to enhance tumorigenesis [243,244] . Simultaneously, the

Another H S and NO donor is NOSH-sulindac. This inhibition of CSE suppresses EMT markers and EGFR
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compound has been shown to induce apoptosis in cancer though ERK1/2 inactivation, thus resulting in cancer
[245]
cells at a relatively lower concentration than normal suppression . Knocking down CSE also increases
cells. The treatment of NOSH-sulindac resulted in over radiosensitivity and reduces radiation-mediated promotion
150 times cell growth inhibition in human breast cancer of EMT by blocking the p38 MAPK pathway [246] . However,
cells MCF-7, pancreatic cancer cells BxPC-3, and colon a recent study has revealed that the inhibition of CSE in
cancer cells HT-29 as compared to its treatment in normal mice negatively regulates the immunosuppressive enzyme
lung cells IMR-90, pancreatic epithelial cells ACBRI 515, indoleamine 2,3-dioxygenase 1, creating an immune-
and normal breast cells HMEpC [236] . Its effect is associated tolerant tumor microenvironment. This event can be
with the suppression of pro-inflammatory TNF-α, reduced by overexpressing CSE or increasing H S levels [247] .
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oxidative marker MDA, the induction of G2/M arrest, This negative correlation can also be confirmed in clinical
and apoptosis [237] . The effect of this donor on colon cells samples. These conflicting results show a need for further
has been reported to be independent of the cell’s ability to studies on cancer and the role of CSE. In colon cancer, the
produce prostaglandin [238] . As of now, no mechanism has activation of Wnt/β-catenin pathway is associated with the
been found to be associated with the inhibitory effect of upregulation of CSE expression.
NOSH-sulindac; hence, the potential of this donor has yet In a study, the proliferation of SW480 cells was
to be determined. significantly reduced by CSE-knockdown, suggesting the
With all the given findings, it is widely recognized enzyme’s potential role in colon cancer metastasis [248] . CSE-
that the treatment with H S donors (exposure of H S) mediated production of H S has been reported to promote
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can inhibit the proliferation of cancer cells, induce the progression of prostate cancer through the activation of
apoptosis, and promote cell cycle arrest, thus resulting in Cav3.2 and IL-1β/NF-Κb cascades, whereas CSE inhibition
cancer cell death (Figure 3). However, there is still room results in anticancer effects in PC-3 cells [249] . Overall, the
for investigation concerning H S donors induction, the above data suggest that CSE inhibitors have the potential
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initiation of cancer cell death signaling, and their causes. to be anticancer drugs in certain types of cancers; however,
Figure 4 is a schematic presentation of exogenous H S- less is still known about their mechanism of action, clinical
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based natural and synthesized chemical compounds used applicability, and possible side effects.
in cancer research.
3.2. CBS inhibitor
3. Targeting endogenous H S for cancer CBS is also a key player in cancer activities. Therefore,
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treatment understanding its inhibition effect on cancer is of
3.1. CSE inhibitor paramount importance. It has been previously reported
that CBS is highly upregulated in gastric cancer tissues
CSE is a major contributor to H S production in numerous compared to non-cancerous ones. Its inhibition with
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cells. Targeting this marker directly affects cell viability amino-oxyacetic acid (AOAA) enhances the anticancer
and progression. For example, CSE has been reported to be effects of 3,3’-diindolylmethane by activating the p38/p53
highly upregulated in breast cancer patients, in which the axis [250] . Similarly, in another study, tissue samples of breast
event positively corresponds to breast cancer metastasis by cancer patients exhibited high levels of CBS compared to
elevating angiogenic factor VEGF and activating various normal tissues. Further examination had revealed that
signaling pathways, such as PI3K/AKT, Ras/Raf/MEK/ silencing CBS causes a significant reduction in cell growth
ERK, and STAT-3 [239] . By knocking down CSE in breast and progression of breast cancer cells [251] . The inhibition
cancer cells, MDA-MB-231 significantly suppresses both of CBS also attenuates the antioxidant pathway Nrf2 and
migration and proliferation activities [240] . Treatment with sensitizes the cells to doxorubicin [252] .
CSE drug inhibitors, such as I157172 and I194496, potently
suppresses CSE activities with pro-cancer events through Besides that, CBS modulates cancer cells by regulating
the promotion of sirtuin 1 and the inhibition of STAT-3, nicotinamide phosphoribosyltransferase and ATP
VEGF/FAK/paxillin, PI3K/AKT, and Ras/Raf/MEK/ERK activities [253] . In HCC patients, low CBS mRNA expression
pathways [241] . Similarly, CSE has a pro-cancer effect in gastric correlates with higher disease progression stages and shorter
cancer; its inhibition prevents cell growth and metastasis overall survival [254] . However, the increased expression of
through promoting apoptosis and improving anticancer CBS as a result of hypoxia-induced radioresistance can
drug sensitivity [242] . SP1-dependent activation of PI3K/ be attenuated following treatment with a CBS inhibitor
AKT pathway in HCC cells has shown that it acts through and AOAA in HepG2 cells [255] . CBS has been found to be

Volume 2 Issue 1 (2023) 15 https://doi.org/10.36922/gpd.v2i1.164