Novel strategies for molecular targeting to cancer

SUMMARY
This editorial draws attention to the work published by CEPP in 2014–2015 on mechanisms underlying cancer drug resistance, invasion and metastasis. Genetic, genomic and immunological changes in platinum drug resistance and new drug candidates for cancer metastasis are highlighted. Atten- tion is paid to the Epimedium plant drug icariin in glioblas- toma invasion, the plant Avicennia marina bioactive compound Naphtho[1,2-b]furan-4,5-dione in breast cancer metastasis, the PI3K inhibitor BEZ235 in colon cancer stem cells, the histone methyltransferase EZH1 inhibitor GSK343 in cervical cancer, and vitamin D3 in prostate cancer.Cancer is the number one killer with highest mortality among human diseases. Research into the mechanisms leading to cancer for early detection and optimal intervention has been a hot topic in clinical and experimental medicine. Recently, molecular phar- macological research has made significant advancement in the processes of cancer resistance to chemotherapy, cancer cell inva- sion and distant metastasis. In the following paragraphs, I discuss the research discoveries in these aforementioned areas published in CEPP in last two years.Harrison and Selemidis hypothesized that reactive oxygen species (ROS) from a myriad of physiological processes is a causative factor in cancer if an excess amount is produced to influence diverse oncogenic processes as well as immune function by oxi- dation and nitration of key macromolecules.1 In their review arti- cle, the authors discussed the family of NADPH oxidase enzymes as the most likely source of ROS in promoting tumori- genesis through the signaling pathways within endothelial, immune and tumor cells.1 The pharmacological inhibitors of NADPH oxidases may thus offer alternatives to suppress tumor angiogenesis by preventing overproduction of ROS as compared with traditional anti-oxidants.1

As a pro-oxidant that induces oxidative stress by generating ROS or inhibiting antioxidant systems, vitamin D at low levels may favor cell proliferation rather than differentiation. Insufficient vitamin D intake has been suggested to be prevalent among men at risk of prostate cancer, and as an active form of vitamin D3, calcitriol may have anti-proliferative and pro-differentiating effects on cancer cells.2 Li et al. reported that vitamin D3 when combined with metformin that is a popular first line anti-diabetic drug and recently anti-aging candidate exhibits a synergistic effect on prostate cancer cell apoptosis.2 Vitamin D3 plus met- formin together induce prostate cancer DU145 cell apoptosis to a level greater than the sum induced by vitamin D3 and met- formin singly.2 While vitamin D3 or metformin alone reduces the levels of c-Myc and has no effect on the levels of phosphorylated mTOR, vitamin D3 and metformin together results in virtually undetectable immunoreactive c-Myc or phosphorylated mTOR by Western blotting.2 The synergistic effect of vitamin D3 and metformin on DU145 cell apoptosis and inhibition of mTOR and c-Myc may implicate an enhanced action from distinct and yet related mechanisms against prostate cancer cell proliferation or/ and survival.In addition to metabolic oncogenic stress, genetic polymorphisms in the genes of HMGB1 and HMGB2 have been found to be associated with lung cancer.3 Wang et al. reported that in 338 lung cancer patients, who received at least two cycles of first-line platinum-based chemotherapy, there were three single nucleotide polymorphisms (SNPs) of HMGB1 and two SNPs of HMGB2. The SNPs rs1412125 and rs2249825 in HMGB1 were signifi- cantly associated with the platinum-based chemotherapy response in both recessive and genotypic models, although rs1412125 was significantly associated with platinum-based chemotherapy response for the subgroup of patients aged > 55 years in additive, recessive and genotypic models.3 So, the HMGB1 SNPs (rs1412125 and rs2249825) are implicated as being an important biomarker for predicting the efficacy of platinum-based chemotherapy.3

Platinum derivatives (cisplatin, carboplatin and oxaliplatin) are chemotherapeutic drugs for treating many cancers. The mecha- nism by which platinum causes cancer cell death involves a direct interaction of the chemical compound with genomic DNA and an adduct formation that triggers cell death. Tsai et al. sug- gested that as the backbone of systemic therapeutic regimens for female cancers over the last two decades, cisplatin enhances anti-tumor immunity by up-regulating the expression of major histocompatibility complex class I (MHC-I) and the cell death receptor Fas in a number of human tumour cells lines, in addition to its cytotoxic actions through intercalating with DNA.4 In vivo treatment of ectopic cervical tumors in mice with metronomic cisplatin suppresses the growth of tumor cells with an increase in the number of splenocytes expressing IFN-gamma and CD8 responsible for E7 tumor antigens and an increase in the Treg population, suggesting that metronomic low-dose cisplatin chemotherapy enhances anti-tumor immunity.4
In lung and colon cancer cell cultures, Jordheim et al. quoted that the platinum-induced DNA adducts are substrates for the DNA repair mechanism nucleotide excision repair (NER), and that strong NER activity in cancer cells opposes the induction of apoptosis in platinum-treated cancer cells and induce resistance to platinum anti-cancer activities.5,6Over-expressing the protein fragments that mediate NER protein interactions in lung cancer A549 increases the lung cancer cell sensitivity to carboplatin 1.2–2.2-fold.5 In colon cancer HCT116 cells, however, over- expressing the protein fragments that mediate NER protein inter- actions increases colon cancer cell sensitivity to oxaliplatin 1.4– 5.4-fold.5 The bifurcation of cancer cell sensitivity to different platinum derivatives induced by interfering NER may represent a new opportunity for mechanistic investigation particularly in reg- ulating the chemotherapeutic intervention.

Another molecular genetic abnormality identified recently as a novel target in cancer is histone methyltransferase EZH2 (Enhan- cer of zeste 2) that is overexpressed in various cancers.7 EZH2 is a component of PRC2 (Polycomb Repressive Complex 2) impor- tant in the initial targeting of the genomic region (PRC Response Elements or PRE) for gene silencing by its methyltransferase activity that catalyzes trimethylation on the lysine-27 of histone H3 (i.e. H3K27me3). Xu and colleagues found that the recently identified EZH2 inhibitor GSK343, which selectively inhibits the trimethylation of the lysine-27 on histone H3 and reactivate silenced genes, induces phenotypic reprogramming of cancer cells from mesenchymal to epithelial cells, reducing the prolifera- tion and motility and blocking the invasion of cervical cancer cell lines in vitro and in vivo.7 Treatment with GSK343 results in increased levels of the epithelial marker E-cadherin and decreased levels of mesenchymal markers such as N-cadherin and vimentin, suggesting that EZH2 is a putative target for reprogramming gene expressions in epithelial-to-mesenchymal transition (EMT) in association with cervical cancer invasion and metastasis. Breast cancer metastasis also represents a poor prognosis and a high mortality. Screening for effective compounds in suppressing tumor invasion has been an important strategy for potential treat- ment and prevention of breast cancer. Tsai et al. reported that while hepatocyte growth factor (HGF) and its receptor tyrosine kinase c- Met played an important part in invasive human breast cancer, the bioactive plant component of Avicennia marina-Naphtho[1,2-b] furan-4,5-dione (NFD) inhibits HGF-induced migration and invasion of MDA-MB-231 human breast cancer cells in a non-toxic con- centration-dependent manner.8 NFD inhibits c-Met phosphorylation and downstream activation of phosphatidylinositol 3-kinase (PI3K), Akt and IkappaB kinases, suggesting a potential utility in interven- tion at an early stage of HGF-driven breast cancer cell migration in the cell culture system.8

Colon cancer as one of the most common cancers world- wide displays frequent drug-resistance and metastasis in associ- ation with high mortality, which have been ascribed to the plasticity of colon cancer stem cells. Wenyi Gu and colleagues show that colon cancer stem cells isolated through sphere cell culture and verified with the cancer stem cell markers CD133, CD44, and CD24 exhibit high levels of PI3K/Akt/mTOR sig- nalling activity and that inhibition of the PI3K/Akt/mTOR pathway with the inhibitor BEZ235 suppresses the colon can- cer stem cell proliferation with reduced stemness and reduction of reduced CD133 and Lgr5.9 Interestingly, inhibition of CD133 expression by BEZ235 is inhibited by insulin known activator of the PI3K/Akt pathway, suggesting that the PI3K/ Akt/mTOR pathway reversibly underpins the stemness of colon cancer stem cells and BEZ235 represents an eligible drug can- didate for treatment of colon cancer drug resistance and metas- tasis by intervening in the PI3K/Akt/mTOR pathway.Glioblastoma is the most aggressive type of glioma account- ing for up to 50% of all malignant primary brain tumors, char- acteristic of extremely aggressive invasion and destructive infiltration with poor prognosis and low survival rate. Given the significant involvement of EMT in the invasiveness of high grade astrocytomas with down-regulated epithelial markers (E- cadherin and ZO-1) and up-regulated mesenchymal markers (vi- mentin and N-cadherin), and the association between high expression of diverse matrix metalloproteinases (MMPs) and tumor invasion with shortened survival in human glioblastoma, Xu et al. examined the effect of icaritin that is a hydrolytic pro- duct of icariin from the genus Epimedium plant on cancer inva- sion and EMT, and found for the first time that icaritin significantly inhibits the invasion and EMT of glioblastoma U87MG cells, by targeting extracellular matrix metalloproteinase (EMMPRIN).10 Furthermore, the authors suggested that the sup- pressive effect of icaritin on EMMPRIN by greater than 50% as demonstrated at both the gene and protein levels is mediated via the PTEN/Akt/HIF-1a signalling pathway, highlighting the potential of icaritin to be employed as a anti-cancer agent in the treatment of GSK343 glioblastoma.