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Page 8 of 17 Wenner et al. J Cancer Metastasis Treat 2020;6:33 I http://dx.doi.org/10.20517/2394-4722.2020.73

Table 3. Summary of autophagic response induced by Withaferin A in various cancer models
Author Year Specimen Cancer Treatment Results
Alnuqaydan et al. [46] 2020 Cell culture, Colorectal WA with 5-FU Inhibited β-catenin pathway and promoted
WS480, HT-29, HCT- G2M cell cycle arrest
116, NCM-460
Liu et al. [48] 2019 Cell culture, MDA- Breast WA Induced mitochondrial apoptosis by
MB-231 increasing Bax levels and decreased Bcl-2
Hsu et al. [44] 2019 Xenograft model; Lung WA and Synergistic effect of WA and pemetrexed,
Cell culture, A549, pemetrexed, cisplatin, or gemcitabine. WA
CL141, H441, CL97, cisplatin, or downregulated mTOR/STAT3 signaling
H1975, CL152, H1299 gemcitabine
Siddharth et al. [57] 2019 Cell culture, Huh7, Liver WA and WA + WA induced autophagy. Combination of
HepG2, MHCC97H, Chloroquine or WA with Chloroquine or Bafilomycin had a
MHCC97L Bafilomycin higher efficacy than monotherapy
Muniraj et al. [50] 2019 Cell Culture, MDA- Breast WA WA inhibited autophagy flux leading to
MB-231 decreased substrates for the TCA cycle
Ghosh et al. [49] 2017 Cell culture, MCF-7, Breast WA WA inhibited tubulin polymerization
MDA-MB-231
Ghosh et al. [47] 2016 Cell culture, MCF-7, Breast WA WA promoted paraptosis
MDA-MB-231
Okamoto et al. [51] 2016 Cell culture, MDS92, Myelodysplasia WA G2/M phase cell cycle arrest
MDS-L and Leukemia
Li et al. [52] 2016 Cell culture, Panc-1, Pancreas WA with cisplatin, WA induced ER stress-mediated apoptosis.
SW1990, MIAPaCa-2, paclitaxel, When combined with cisplatin, paclitaxel,
AsPC-1, BxPc-3 epirubicin or epirubicin or TNFSF10, this effect was
TNFSF10 increased
Nishikawa et al. [53] 2015 Cell culture, PC-3, DU- Prostate WA WA showed an increase in mRNA and
145, TIG-1, KD, LNCaP protein levels of c-Fos
Rah et al. [54] 2015 Cell culture, PC-3, DU- Prostate AWA- Derived WA treatment resulted in autophagy and
145 from WA apoptosis
Vyas et al. [55] 2014 Cell culture, PC-3, Prostate, breast, WA Inhibited oncogenic signaling pathways,
MDA-MB-231, DRO81- thyroid, soft tissue specifically F-κB, Akt, signal transducer
1, HT-1080, 4T1, CaSki, sarcoma, cervical, and activator of transcription 3 (Stat3) and
AB12, Panc-1 pancreatic, estrogen receptor-α (ER-α)
mesothelioma
Hahm et al. [56] 2013 Cell culture, MDA- MB- Breast WA WA treatment resulted in autophagy
231, MCF-7, MCF-10A
Kakar et al. [43] 2012 Cell culture, Ovarian WA and cisplatin The combination of treatment synergistically
A2780, A2780/ CP70 enhanced antitumor effects of cisplatin
Fong et al. [45] 2012 Cell culture, A2780, Ovarian WA and The combination of treatment induced
A2780/ CP70, CAOV3 Doxorubicin apoptosis and enhancement of ROS
production causing DNA damage

WA: Withaferin A; mTOR: mammalian target of rapamycin; ROS: reactive oxygen species

c-FLIP (L) was also observed in the study . When prostate cancer cells were treated with 3-AWA, an azido
[53]
derivative from WA, LC3B-I was converted to LC3B-II, stimulating autophagy and eventually, apoptosis.
Prostateapoptosis response-4 (PAWR or Par-4) is a protein closely associated with tumor-suppressing
activity, and right before apoptosis, PAWR levels are elevated. When PAWR is overexpressed in a cell,
it induces apoptosis by inhibiting the antiapoptotic protein BCL2 by binding to Wilms tumor 1 protein
(WT1). This study found that because PAWR binds to WT1, it indirectly downregulates BCL2 expression
[54]
and suppresses Beclin 1, an essential component in autophagy . WA has been shown to target oncogenic
signaling pathways, specifically NF-κB, Akt, Stat3, and estrogen receptor-α (ER-α). In human cancer cells,
these pathways are often hyperactive; however, WA has been shown to inhibit their activity. WA was shown
to inhibit the NF-κB pathway by nuclear translocation of the p65 subunit of NF-κB and or downregulation
of p6 in prostate cancer cells and soft tissue sarcoma cells. Suppression of ER-α by WA in breast cancer cells
[55]
can lead to apoptosis. Cells treated with WA showed downregulated ER-α protein, leading to apoptosis .
Upon exposure to WA, MDA-MB-231 and MCF-7 breast cancer cells underwent autophagy, which was
confirmed by analysis of acidic vesicular organelles and cleavage and recruitment to autophagosomes
of LC3-II . WA-induced autophagy was shown to be cytoprotective in hepatic cells, and by inhibiting
[56]
[57]
its cytoprotective effects with chloroquine, tumor cells became more responsive to therapy . Table 3
summarizes the WA-induced autophagic response in different cancer models.