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Page 4 of 17 Wenner et al. J Cancer Metastasis Treat 2020;6:33 I http://dx.doi.org/10.20517/2394-4722.2020.73

Table 1. Summary of autophagic response induced by PEITC in various cancer models
Author Year Specimen Cancer Treatment Results
Wang et al. [29] 2018 Cell culture: A549, Lung PEITC, Combination therapy enhanced the inhibitory effect
H661 and SK-MES-1; 3-MA, of PEITC on metastasis potential of lung cancer cells
lung cancer xenograft chloroquine
Singh et al. [23] 2018 Cell culture, LNCaP Prostate PEITC Inhibited PCa growth bye c-Myc overexpression
and 22Rv1 cells
Zhang et al. [30] 2016 Cell culture, LNCaP Prostate PEITC Suppressed cell proliferation through the MMP2/
cells MMP9 pathway
Xue et al. [19] 2014 Cell culture, LNCaP Prostate PEITC PEITC increased the number of smooth ER vacuoles.
cells Within 18 h of exposure, mitochondrial membrane
potential was disrupted
Yu et al. [14] 2013 Cell culture, LNCaP Prostate PEITC Inhibited AR-regulated transcriptional activity and
cells growth of PCa cells
Powolny et al. [18] 2011 Transgenic mouse Prostate PEITC Suppressed prostate cancer progression by induction
model (TRAM) of autophagic cell death
Xiao et al. [20] 2010 Cell culture, LNCaP Prostate PEITC Induced autophagy through ROS
and PC-3 cells
Bommareddy et al. [17] 2009 Cell culture, PC-3 and Prostate PEITC, 3-MA Induced apoptotic and autophagic cell death
LNCaP cells
PEITC: phenethyl isothiocyanate; ROS: reactive oxygen species; ER: estrogen receptor; AR: androgen receptor

also been shown that MMP2 and MMP9 proteins are both highly expressed in breast cancer tissues and are
[27]
related to lymph node metastasis and tumor staging . These results further prove that the regulation of
miR-194 and MMP2 and MMP9 proteins is critical in cancer research and that PEITC’sability to modulate
the expression of these factors is vital in the induction of autophagy and prevention of metastasis. Table 1
summarizes the PEITC-induced autophagic response in different cancer models.

CAPSAICIN
Plants belonging to the genus Capsicum synthesize the alkaloid capsaicin (CAP), known to give chili
peppers their hot, spicy flavor . Despite being an important cultural ingredient in many cuisines,
[31]
CAP possesses anticancer properties, which have become an area of scientific interest in regard to
chemoprevention. Studies have aimed at elucidating the mechanisms in which CAP works to promote
autophagy in cancer cells to foster clinical applications for cancer treatment.

Researchers have discovered that coupling CAP with other chemotherapeutic drugs can minimize cellular
chemoresistance to conventional therapies. A study investigating the combination of CAP and cisplatin
against human osteosarcoma (HOS) cells showed that CAP at lower concentrations and cisplatin displayed
a synergistic reduction of cellular viability in MG63, 143B and HOS cell lines . This study further
[32]
showed cell cycle arrest in the G0/G1 phaseand also examined the association of MMPs with inhibition
of cellular invasion. The combination treatment resulted in decreased expression of MMP-2 and MMP-9
and reduced gelatin degradation by these enzymes. The study also investigated whether CAP/cisplatin
treatment induced autophagy. Expression of the autophagy-associated proteins Beclin 1, Atg3, Atg5, Atg16,
and LC3-II was increased along with the accumulation of autophagic vacuoles in the cytoplasm, indicating
autophagy induction. CAP/cisplatin treatment was shown to target the reactive oxygen species (ROS)/
AKT/mTOR pathway, a crucial mediator of cellular autophagy, by reducing p-ATK and p-mTOR levels.
Upon treatment with the autophagy inhibitor bafilomycin (BAF), cells exhibited upregulation of apoptotic
genes, suggesting that autophagy may be a pro-survival mechanism in osteosarcoma (OS) cells. CAP/
cisplatin treatment significantly increasedthe generation of ROS, found to mediate the activation of the
JNK pathway. In addition to reducing the cytotoxic effects of the combination treatment, pretreatment of
HOS cells with N-acetyl cysteine (NAC), an ROS scavenger, reduced JNK phosphorylation and partially
[32]
suppressed autophagy by reversing p-ATK and p-mTOR reduction . Another study examined the effects
of CAP on the sensitivity of cholangiocarcinoma (CCA) cells to common chemotherapeutic drugs. The