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

as well as disrupts microtubules to promote apoptosis with NAC, however, may restore pro-cancer properties
and anti-migratory events [157] . In colon cancer, PEITC following treatment with anticancer drugs that initially
inhibits NF-κB, AKT, ERK, and JNK to mediate anticancer work by raising ROS levels, such as piperlongumine.
properties [158] . The treatment of ovarian cancer cells with Meanwhile, the combination of NAC with bromelain
PEITC has revealed that the latter exhibits pro-apoptotic shows more potency in inhibiting the growth of
activities through the activation of caspases, p38, and JNK, gastrointestinal cancer by facilitating caspase-dependent
and the inactivation of AKT/ERK1/2 and CRM1-mTOR/ apoptosis and autophagy [171] . Moreover, a clinical trial
STAT3 pathways [159] .
has revealed that the administration of NAC can reduce
In lung cancer, PEITC treatment promotes G2/M arrest, oxaliplatin-induced neuropathy in CRC and gastric cancer
elevates cleaved caspase-3, PARP, GADD153, endonuclease patients [172] . In lung cancer, individual treatment with NAC
G, and Bax, and inactivates the Janus kinase 2 (JAK2)/ has pro-cancer effects that are associated with reduced
STAT3 pathway, thus facilitating cell death and reducing ROS, p53 activity, and DNA damage; however, when
migration activities [160] . In melanoma, PEITC induces cell administered in combination with other therapeutics,
death through the activation of mitochondria apoptosis it shows solid anticancer activities [173] . NAC enhances
and the elevation of ROS level [161] . Moreover, PEITC glioblastoma cell death in an antioxidant-independent
administration suppresses Bcl-2 and Bcl-xL, elevates Bak, manner by facilitating lysosomal degradation of Notch 2
inhibits Notch 1 and 2 cascades in pancreatic cancer, and cascade, thus resulting in the attenuation of the pathway [174] .
inhibits Wnt/β-catenin in CRC [162] . In prostate cancer, In gastric cancer cells, NAC can effectively attenuate ROS-
PEITC treatment decreases the expressions of CDK1, induced apoptosis, triggered by anticancer drugs like
cyclin B1, CDC25C, α/β-tubulin, surviving, and XIAP, and curcumin [175] .
increases the expressions of miR-194, caspases, p53, and
WEE1 to mediate anticancer activities [148] . Furthermore, In human breast cancer MDA-MB-435 cells, treatment
PEITC induces cell apoptosis in breast cancer cells with NAC induces cell death and vascular collapse by
promoting apoptosis and the production of antiangiogenic
through the elevation of p53, the suppression of ER-α36, mediator angiostatin, as well as shifting estrogen
metadherin, HER2, EGFR, and STAT-3 expressions, and metabolism by inhibiting the formation of DNA adducts [176] .
the reactivation of cadherin [148,163] . The above data suggests In addition, NAC suppresses cancer proliferation by
that PEITC has potential in cancer treatment; however, attenuating Ki67 expression and the glycolysis marker
little is known concerning the drug’s mode of action and [177]
clearance mechanism. stromal monocarboxylate transporter 4 . However, there
have been conflicting studies, wherein NAC treatment,
2.1.11. N-acetyl cysteine (NAC) combined with other potential anticancer drugs, can either
enhance or suppress the drug’s cytotoxicity [178] . The mode
NAC is a H S donor and a precursor for L-cysteine and of action of the treatment plays a key role in determining
2
reduced GSH. It is a cytoprotective compound with potent the synergistic effect of NAC. In a recent clinical trial, oral
antioxidant properties [164] . NAC-derived cysteine releases administration of NAC in breast cancer patients effectively
H S in the mitochondria, elevating 3-MPST and sulfide
2
quinone oxidoreductase (SQR), which are the potential reduced paclitaxel-induced peripheral neuropathy and
improved the quality of life in these patients
. Moreover,
[179]
upstream regulators of sulfane sulfur species [165] . In a NAC treatment also exhibits anticancer effects in bladder
recent study, NAC has been shown to serve as a substrate cancer linked with the activation of caspases, cell cycle
for 3-MPST and SQR in colon cancer cells. However, arrest, and suppression of metastasis through MMP-2
the event did not significantly alter their viability and downregulation [180] . In bladder cancer, the co-treatment
rate of proliferation [166] . In contrast, NAC-mediated of cis-dichlorodiammineplatinum and GSH with NAC
elevation of 3-MPST activities and intracellular H S level
2
exhibits antiproliferative properties in neuroblastoma significantly reduces ROS generation from the initial
[181]
cells (SH-SY5Y) [167] . Besides, NAC can reverse the anti- treatment, suggesting the restoration of carcinogenesis .
tumor effect of xanthatin, including G2/M arrest and In prostate cancer, NAC treatment suppresses cancer
ROS-mediated autophagy and apoptosis, in colon cancer metastasis through ROS regulation, CYR61 upregulation,
cells [168] . In gastric cancer, NAC promotes SJ-89 cell NF-κB inhibition, and the partial activation of AKT and
cycle arrest, apoptosis, and DNA damage [169] . Further ERK1/2 [182] . In addition, the pro-inflammatory effects of
evidence has shown that NAC treatment can suppress the cisplatin and etoposide (VP-16) may be suppressed by
metastasis and glycolysis of gastric cancer cells, resulting NAC [183] . Besides, in ovarian cancer, the cotreatment of
from autophagy inhibition-mediated ROS, through the doxorubicin with NAC enhances its anticancer effect, which
deactivation of NF-κB and HIF-1α [170] . Cotreatment is associated with ATM/p53 pathway activation and mTOR

Volume 2 Issue 1 (2023) 11 https://doi.org/10.36922/gpd.v2i1.164