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Page 2 Li et al. J Transl Genet Genom 2021;5:163-72 https://dx.doi.org/10.20517/jtgg.2021.22

and kavalactones showed a significant inhibition of LSD1 and MAO-A enzyme activities.

Conclusion: Our results suggest that consumption of kava products through diet can delay prostate cancer
development and progression and that kavalactones may be a new structure model for developing a potent dual
inhibitor of LSD1 and MAO-A.

Keywords: Kava, chemoprevention, LSD1, MAO-A

INTRODUCTION
Prostate cancer has a projected incidence of ~248,530 new cases diagnosed, accounting for ~34,130 deaths
[1]
in 2021 in the United States, ranking the second leading cause of cancer death in men . The majority of
men diagnosed with prostate cancer (about 4 in 5 men) die from other reasons rather than prostate cancer.
[1]
More than 3.1 million men are alive with a diagnosis of prostate cancer in the United States . In addition,
over one-third of prostate cancer is slowly growing or progressing over several decades. This group of
[2]
patients without cancer-related symptoms do not warrant aggressive, immediate treatment . Instead, they
are closely monitored for their indolent status using prostate-specific antigen (PSA) kinetics, periodic
biopsies for histologic progression, and possibly surveillance magnetic resonance imaging (MRI) until
further treatment is needed as judged by physicians. This emergent strategy for the management of indolent
prostate cancer is called active surveillance . Men on active surveillance have high anxiety, depression and
[2]
doubts about the possible progression of the disease and are highly motivated to prevention approaches
using dietary or pharmacological means or positive lifestyle changes . Therefore, men on active surveillance
[3]
have been thought to be an ideal population for chemo/dietary prevention methods to further reduce
disease progression and anxiety during the period of active surveillance. Currently very few
chemopreventive agents are effective for their testing in chemoprevention studies in this population.

Kava (Piper methysticum Forst) is a continually regrowing shrub native to the South Pacific Islands .
[4]
Traditionally, kava root extracts (KRE) have been prepared with coconut milk and water as a drink for a
[4]
social gathering in the Pacific Islands for thousands of years . The kava drink improves sleep quality and
produces distinct muscle relaxation without drug addiction . Several clinical studies have shown
[4]
[5-7]
commercially available KRE to reduce anxiety and sold as an anxiolytic agent for several decades . Kava
drinking was also linked to lower cancer risk by an epidemiological study . In addition, KRE has
[8]
demonstrated potent anti-carcinogenic activity in several cancers, including bladder cancer, lung cancer,
and others [9-12] . Intriguingly, compared to other areas of the world, incidences of prostate cancer in kava
drinking countries, such as Fiji, are very low. However, when Fijian men moved to Australia, their prostate
cancer incidence raised by 5.1-fold [13,14] . These results have led us to investigate whether kava consumption
can affect prostate cancer development and progression. We have previously shown that oral administration
of KRE through dietary supplementation effectively reduced the growth of patient-derived xenograft (PDX)
tumors and down-regulated the protein levels of androgen receptor (AR) and the expression of AR target
genes PSA and transmembrane protease, serine 2 (TMPRESS2) . Given the above-described properties of
[9]
KRE, KRE would have the promise to be further studied as a chemopreventive agent for reducing
progression risk and anxiety in prostate cancer patients under active surveillance.

To evaluate the chemopreventive effect of KRE, transgenic adenocarcinoma of the mouse prostate
(TRAMP) mice were administrated with vehicle control or KRE formulated food in different stages of
tumor development to test its ability to prevent prostate cancer development [i.e., occurrence of high-grade
prostatic intraepithelial neoplasia (HG-PIN) and prostate adenocarcinomas] or delay progression. In
addition, the effects of the KRE and its main components of kavalactones, including kawain,