Increasing studies have reported that cancer stem cells (CSCs) play critical roles in therapeutic resistance, recurrence, and metastasis of tumors, including cervical cancer. Pterostilbene, a dimethylated derivative of resveratrol, is a plant polyphenol compound with potential chemopreventive activity. However, the therapeutic effect of pterostilbene against cervical CSCs remains unclear. In this study, we compared the anticancer effects of resveratrol and pterostilbene using both HeLa cervical cancer adherent and stem-like cells. Pterostilbene more effectively inhibited the growth and clonogenic survival, as well as metastatic ability of HeLa adherent cells than those of resveratrol. Moreover, the superior inhibitory effects of pterostilbene compared to resveratrol were associated with the enhanced activation of multiple mechanisms, including cell cycle arrest at S and G2/M phases, induction of ROS-mediated caspase-dependent apoptosis, and inhibition of matrix metalloproteinase (MMP)-2/-9 expression. Notably, pterostilbene exhibited a greater inhibitory effect on the tumorsphere-forming and migration abilities of HeLa cancer stem-like cells compared to resveratrol. This greater effect was achieved through more potent inhibition of the expression levels of stemness markers, such as CD133, Oct4, Sox2, and Nanog, as well as signal transducer and activator of transcription 3 signaling. These results suggest that pterostilbene might be a potential anticancer agent targeting both cancer cells and cancer stem-like cells of cervical cancer via the superior bioavailability to resveratrol.

Glioblastoma multiforme (GBM) is the most aggressive and common type of human primary brain tumor. Glioblastoma stem‐like cells (GSCs) have been proposed to contribute to tumor initiation, progression, recurrence, and therapeutic resistance of GBM. Therefore, targeting GSCs could be a promising strategy to treat this refractory cancer. Calmodulin (CaM), a major regulator of Ca2+‐dependent signaling, controls various cellular functions via interaction with multiple target proteins. Here, we investigated the anticancer effect of hydrazinobenzoylcurcumin (HBC), a Ca 2+/CaM antagonist, against GSCs derived from U87MG and U373MG cells. HBC significantly inhibited not only the self‐renewal capacity, such as cell growth and neurosphere formation but also the metastasis‐promoting ability, such as migration and invasion of GSCs. HBC induced apoptosis of GSCs in a caspase‐dependent manner. Notably, HBC repressed the phosphorylation of Ca 2+/CaM‐dependent protein kinase II (CaMKII), c‐Met, and its downstream signal transduction mediators, thereby reducing the expression levels of GSC markers, such as CD133, Nanog, Sox2, and Oct4. In addition, the knockdown of CaMKIIγ remarkably decreased the cancer stem cell‐like phenotypes as well as the expression of stemness markers by blocking c‐Met signaling pathway in U87MG GSCs. These results suggest that HBC suppresses the stem‐like features of GBM cells via downregulation of CaM/CaMKII/c‐Met axis and therefore CaMKII may be a novel therapeutic target to eliminate GSCs.

Flavonoids are one of the predominant groups of plant polyphenols, and these compounds have significant effects on human health and nutrition. Sulfated flavonoids have more favorable attributes compared to their parent compounds such as increased solubility, stability, and bioavailability. In this research, we developed a microbial system to produce sulfated naringenin using Escherichia coli expressing a sulfotransferase (ST) from Arabidopsis thaliana (At2g03770). This wild-type strain was used as a model system for testing clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) metabolic engineering strategies. Using synthetic sgRNA to mediate transcriptional repression of cysH, a gene encoding 3′-phosphoadenosine-5′-phosphosulfate (PAPS) ST, which is involved in sulfur metabolism, resulted in an increase in intracellular PAPS accumulation by over 3.28-fold without impairing cell growth. Moreover, naringenin 7-sulfate production by engineering E. coli with its cysH gene repressed in the open reading frame through CRISPRi was enhanced by 2.83-fold in compared with the wild-type control. To improve the efficiency of biotransformation, the concentration of SnormalO42−, glucose, and substrate were optimized. The bioproductivity of naringenin 7-sulfate was 135.49 μM [∼143.1 mg (47.7 mg L-1)] in a 3-L fermenter at 36 h. These results demonstrated that the CRISPRi system was successfully applied for the first time in E. coli to develop an efficient microbial strain for production of a sulfated flavonoid. In addition, antibacterial and anticancer activities of naringenin 7-sulfate were investigated and found to be higher than the parent compound.

Hepatocellular carcinoma (HCC) is a malignant type of primary liver cancer with high incidence and mortality, worldwide. A major challenge in the treatment of HCC is chemotherapeutic resistance. It is therefore necessary to develop novel anticancer drugs for suppressing the growth of HCC cells and overcoming drug resistance for improving the treatment of HCC. Violacein is a deep violet-colored indole derivative that is produced by several bacterial strains, including Chromobacterium violaceum, and it possesses numerous pharmacological properties, including antitumor activity. However, the therapeutic effects of violacein and the mechanism underlying its antitumor effect against HCC remain to be elucidated. This study is the first to demonstrate that violacein inhibits the proliferation and stemness of Huh7 and Hep3B HCC cells. The antiproliferative effect of violacein was attributed to cell cycle arrest at the sub-G1 phase and the induction of apoptotic cell death. Violacein induced nuclear condensation, dissipated mitochondrial membrane potential (MMP), increased generation of reactive oxygen species (ROS), activated the caspase cascade, and upregulated p53 and p21. The anticancer effect of violacein on HCC cells was also associated with the downregulation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2 signaling. Violacein not only suppressed the proliferation and formation of tumorspheres of Huh7 and Hep3B cancer stem-like cells but also reduced the expression of key markers of cancer stemness, including CD133, Sox2, Oct4, and Nanog, by inhibiting the signal transducer and activator of transcription 3 (STAT3)/AKT/ERK pathways. These results suggest the therapeutic potential of violacein in effectively suppressing HCC by targeting the proliferation and stemness of HCC cells.

Background This study was focused on the measurement of anticancer properties of six medicinal plants from western Nepal in three cell lines; HeLa, Hep3B, and HCT116, and anti-inflammatory properties in RAW 264.7 cell line through NO, PGE2, and TNF-α production. In addition, the phytochemical screening, total phenolic, flavonoid content, and antioxidant properties were evaluated. Results The qualitative phytochemical analysis revealed the presence of different secondary metabolite and range of total phenolic and total flavonoid content. The highest antioxidant activities were observed in Bergenia pacumbis against both DPPH (IC50 = 25.97 ± 0.19 μg/mL) and ABTS (IC50 = 14.49 ± 0.40 μg/mL). Furthermore, the highest antiproliferative effect against cervical, liver, and colon cancer cell lines were observed in Melia azedarach as IC50 values of 10.50, 5.30, and 1.57 μg/mL respectively, while the strongest anti-metastatic potential on liver cancer cell line was found in Pleurospermum benthamii. In addition, P. benthamii showed the most potent anti-inflammatory effect in RAW264.7 murine macrophage cells. Conclusion This study provided the evidence for M. azedarach and P. benthamii to have great anticancer potential and finding builds the enough scientific backgrounds in future to isolate and purify the bioactive compounds for further applications.