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Page 10 of 17 Wenner et al. J Cancer Metastasis Treat 2020;6:33 I http://dx.doi.org/10.20517/2394-4722.2020.73
[66]
a different compound in lowering tumor burden has been reported for various cancers. Nakamura et al.
showed synergistic antitumor effect by co-treatment with indole-3 carbinol and genistein against human
colon cancer HT-29 cells. The antitumor effects were attributed to induction of apoptosis via inhibition
of Akt phosphorylation and progression of autophagy. In a different study that useda combination of
genistein and LC3 shRNA plasmid transfection, it was shown that the combination inhibited rapamycin-
induced autophagy and promoted apoptosis in human malignant neuroblastoma SK-N-BE2 and IMR-32
[67]
cells both in vitro and in vivo . Malignant neuroblastoma is an extracranial solid tumor that usually
occurs in children. Autophagy serves as a pro-survival mechanism in malignant neuroblastoma and usually
deters the efficacy of conventional chemotherapeutic agents. The study revealed a decrease in expression
of autophagy-related markers including LC3 expression and Beclin1 levels, and also modulated the
expression of the apoptosis regulatory proteins Bax (pro-apoptotic) and Bcl-2 (anti-apoptotic) essentially
to increase the Bax: Bcl-2 ratio to trigger the mitochondrial pathway of apoptosis . Most recently, a study
[67]
that developed genistein-PEGylated silica hybrid nanoparticles against colorectal cancer showed that
the genistein-based nanoparticles exerted improved antiproliferative effects by modulating antioxidant
enzymatic activity and oxidative stress levels in human colon cancer HT29 cells. Furthermore, cells treated
with the nanoparticles exhibited characteristics of autophagy and resulted in autophagic as well as apoptotic
[68]
cell death without any side effects .
Radiotherapy continues to be an important treatment approach for several cancers. Genistein was shown
to enhance the efficacy of radiation therapy in various cancer types. In a study employing non-small cell
lung cancer (NSCLC) cells, genistein was shown to enhance cellradiosensitivity by inducing apoptotic and
autophagic cell death. The findings revealed the role of genistein in enhancing radiosensitivity by increasing
DNA damage, inhibiting cytoplasmic distribution of Bcl-xL and dissociation of Beclin1 from Bcl-xL to
[69]
induce apoptosis and autophagy, respectively .

In addition to the beneficial effects discussed above, either alone, with estrogen receptor modulator
(tamoxifen) or radiotherapy, genistein has also been found to increase the potency of several traditional
cytotoxic chemotherapeutic agents. For example, a recent study showed that genistein potentiated arsenic
trioxide (As O ) treatment of acute promyelocytic leukemia induced apoptosis and autophagy with the
2
3
combination treatment. The study revealed that genistein in combination with As O was able to increase
3
2
[70]
the total release of ROS andalso the expression ratio of LC3-II/LC3-I in NB4 cells . In a similar study,
both cisplatin-sensitive A2780 and cisplatin-resistant ovarian cancer cells were treated with genistein
alone. The findings revealed that genistein inhibited AKt kinase, which is an oncogenic kinase that plays an
important part in glucose uptake. The resulting low glucose intracellular environment induced autophagy,
[71]
which was evident by an increase inLC3-II levels . In a different study, genistein was used to treat uterine
leiomyoma (UtLM) cells, in which MAP1LC3A was used as a marker to determine an autophagic response.
The findings revealed induction of autophagy and subsequent apoptotic cell death by genistein in UtLM
[72]
cells 72 hours after treatment . Table 4 summarizes the genistein-induced autophagic response in different
cancer models.

Other major phytochemicals known to induce autophagic response
In addition to the four phytochemicals discussed in the current review, several other phytochemicalshave
[11]
been found to induce autophagic response in various cancer models. For example, curcumin , a
polyphenolic compound present in turmeric, was shown to induce autophagic cell death in malignant
glioma cells by inhibiting the Akt/mTOR/p70S6k pathway and activating the ERK1/ERK2 pathway [73,74] . A
most recent study showed that combination of mTORC1/2 inhibitor with curcumin induced autophagy-
mediated cell death by reducing the expression of Rictor and Akt in renal carcinoma, in vitro and in a
[12]
[75]
xenograft model . Similarly, resveratrol , another major polyphenolic compound present in various natural
products including grapes, is well known for its antitumor effects in various cancer models, both in vitro