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Page 20 of 36 Dave et al. J Cancer Metastasis Treat 2020;6:46 I http://dx.doi.org/10.20517/2394-4722.2020.106

in the geometrical isomers of lycopene may be due to factors such as the higher bioavailability of cis vs.
trans [251,252] , greater thermodynamic stability of cis isomers at elevated temperature [253] , and endogenous
isomerization, which may or may not be enzymatic [254] .

Cleavage of β-carotene gives homologous carbonyl products [255,256] ; the pathway was confirmed by the
identification of BCO2 in zebra fish, ferrets, mice and humans [257,258] . BCO2, an enzyme derived from
mitochondria [259] , is mainly expressed in testis and liver, with a comparatively lower amount found in
lung, heart, brain, colon, stomach, intestine, prostate, spleen, and kidney [257,258] . In a study conducted with
humans with lycopene, plasma of those who consumed tomato juice was found to contain apo-6-, apo-8’-,
apo-10’-, apo-12’-, and apo-14’-lycopenal [260] . Moreover, it was reported that non-provitamin A carotenoids,
including zeaxanthin and lutein, are preferentially cleaved relative to provitamin A carotenoids, which
indicates a major role of BCO2 in the metabolism of non-provitamin A carotenoid [258,261] . In another
investigation with humans given lycopene, a series of apo-lycopenals were identified in plasma, including
apo-10’-lycopenal [260] . However, it is not known whether these metabolites are enzymatically cleaved or
products originating due to chemical oxidative cleavage [260] .

In a single blind, randomized, placebo-controlled study, lycopene supplements of 15 mg two times a day
for 3 weeks (Lyc-O-Mato™, LycoRed, Beer-Sheva, Israel) were given to 15 of 26 men who were scheduled
for radical prostatectomy due to organ confined malignancy. Over 3 weeks, in those taking lycopene
supplements, a 22% increase in tissue and plasma levels and a statistically significant reduction in PSA
was observed. Tumor volume was reduced. In addition, cellular proliferation biomarkers were decreased
whereas cellular differentiation markers including connexin 43 and apoptosis were increased with
intervention [262] . In another study, it was reported that combined intake of tomato sauce, tomatoes, tomato
juice, and pizza decreased the risk of prostate cancer [263] . These findings suggest that tomato-based foods
may be beneficial for prostate cancer.

CONCLUSIONS AND FUTURE DIRECTIONS
We currently review some well-studied phytochemicals with cancer chemopreventive potential. Of course,
many other cancer chemopreventive agents are known, either naturally occurring or synthetic, such as
genistein [264] , 6-gingerol [265] , diallyl disulfide [266] , lupeol [267] , honokiol [268] , plumbagin [269] , ellagic acid [270] , and
quercetin [271] , but our arbitrary selection mainly focuses on agents found in the diet with strong evidence
of bioactivity. Numerous studies have been completed or are ongoing with these compounds; copious
amounts of data have been generated. As one example, more than 20,000 articles were disclosed when
searching “resveratrol” as a topic on Web of Science (accessed on August 25, 2020), and there is no doubt a
search involving other chemopreventive agents would reveal a multitude of publications as well. Given this
huge corpus of data, and taking into account the current state of science, there is now an opportunity to
further expand the field of chemoprevention. We currently suggest three such paradigm shifts, referred to
as omics, indirectness, and sequelae.

Omics
The traditional dogma for the discovery of drug candidates is based on “one drug-one target”, where the
goal is to find highly selective agents with one molecular target (or biomarker). The concept is to minimize
adverse effects caused by off-target responses. However, this approach is disingenuous. First of all, an agent
functioning in such a manner would be highly susceptible to failure due to the possibility of developing
drug resistance. Moreover, signaling pathways are exceedingly linked via interconnected networks (cf.
Figure 9). A small change in one target can result in multiple changes in other pathways, akin to the so-
called Butterfly Effect (“Does the Flap of a Butterfly’s Wings in Brazil Set Off a Tornado in Texas?”) [272] ;
Also, the genesis of cancer is comprised of multiple factors, not a single specific element. This is further
complicated by a host of endogenous (e.g., aging, genetic susceptibility, DNA repair machinery, hormones,