## 5 Biological Activities of Zerumbone (ZER)
### Anticancer Activity  
Cancer is one of the leading causes of death worldwide [91]. Various studies have evaluated the anticancer potential of zerumbone. It was assessed against HeLa cell line and interestingly it showed a selective inhibition of HeLa cells proliferation (IC\({}_{50}\) of 14.2 \(\pm\) 0.5 umol/L) via enhancement of cellular uptake compared to the normal cell line L929 [92]. Moreover, [PERSON] and co-workers revealed the anticancer mechanism of ZER on three cell lines including HeLa, B16F10 and undifferentiated Caco-2 cell lines. It was shown that ZER altered the total lipid and fatty acid profile in cancer cells, inducing marked changes in the phospholipid/cholesterol ratio [93]. In addition, the anticancer activity was assessed on Jurkat cells, human T cell leukemia, and it was found that ZER-pendant derivatives showed antiproliferative effects (IC\({}_{50}\) values as low as 1-10 um for most derivatives) [94]. A recent study reported that ZER inhibited cell migration of human esophageal squamous cancer by suppressing Rac1 expression, which is achieved through promoting Rac1 ubiquitination and degradation [95]. Wide number of studies had reported the in vivo, in vitro and in silico anticancer activities of ZER. Herein, an in vivo study showed that ZER significantly controls the growth of tumor and metastasis in BALB/c female mice injected with 4T1 (6-thioguanine resistant cell line) to spontaneously produce highly metastatic tumor [96]. [PERSON] et al. reported the anticancer activity of ZER against colorectal cancer cells, where they showed that ZER activates caspase 3, caspase 8, and caspase 9. ZER resulted in cell cycle arrest at the G2/M phase [97]. Similarly, other study reported induction of apoptosis in hepatoma HepG2 cells by ZER [98]. [PERSON] and co-workers attempted to explore the underlying mechanism of ZER against breast cancer using in silico study. Since estrogen mediates several pathophysiological signaling pathways associated with cancer progression, the author had selected estrogen as a target for breast cancer and found that the promising molecular interaction, binding interaction, and stability of ZER and estrogen receptor-\(\beta\) (ER\(\beta\)) suggests ZER as lead compound for breast cancer [99]. More details of these activities are given in Table 2.  
\begin{table}
\begin{tabular}{l l l} \hline \hline \multicolumn{1}{c}{**Experimental Models**} & \multicolumn{1}{c}{**Results and Possible Mechanisms**} & \multicolumn{1}{c}{**Reference**} \\ \hline \multirow{6}{*}{HeLa cells} & ZER selectively inhibited the proliferation of HeLa cells & \\  & and also enhanced the anti-proliferative activity of & [92] \\  & anticancer agents vinblasting and paclitaxel. & \\  & ZER stimulated the apoptosis. & [100] \\  & Non-small cell lung cancer (NSCLC) & ZER showed suppression of OPN induced cell invasion & [101] \\  & A549 cells & through inhibition of FAK/AKT/ROCK pathway. & [101] \\  & ZER induced mitochondrial apoptosis and enhanced & \\  & the susceptibility to cisplatin. & [102] \\  & ZER exerted anticancer effects against hormone & \\  & refractory DV145 prostate cancer cells & \\  & the inhibition of aberrant signaling axis of & \\  & IL-6/JAK2/STAT3. & \\  & ZER suppressed IL-1ß induced cell invasion. & [104] \\  & ZER exred antimetastatic effects through inhibition of & \\  & FAk/PI3k/NF+kB-uPA signaling pathway. & [105] \\  & ZER inhibited the growth of P-338D1 and HL-60 cells & \\  & and prolonged the life of P-338D1-bearing CDF1 mice. & \\  & ZER induced apoptosis through p53 signal pathway. & [107] \\  & Cytotoxicity of ZER against estrogen receptor positive & \\  & breast cancer (MCF-7) cells & \\  & through co administration with TP5+iRGD peptide. & \\  & CZER showed apoptotic activity on T-acute lymphoblastic & \\  & leukemia. & [109] \\  & PC-3 and DU-145, two human & \\  & hormonerefractory prostate cancer & \\  & (HRPC) cell lines & \\  & HCT-116 and SW-48 cells & \\  & & \\  & Jurkat cells & \\  & Esophageal squamous cell carcinomas & \\  & (ESCC) & \\  & &  
* _Cont._