Intratumor heterogeneity (ITH) is considered the major disorienting factor in cancer treatment. As a result of stochastic genetic and epigenetic alterations, the appearance of a branched evolutionary shape confers tumor plasticity, causing relapse and unfavorable clinical prognosis. The growing evidence in cancer discovery presents to us “the great paradox” consisting of countless potential targets constantly discovered and a small number of candidates being effective in human patients. Among these, cyclic-AMP response element-binding protein (CREB) has been proposed as proto-oncogene supporting tumor initiation, progression and metastasis. Overexpression and hyperactivation of CREB are frequently observed in cancer, whereas genetic and pharmacological CREB downregulation affects proliferation and apoptosis. Notably, the present review is designed to investigate the feasibility of targeting CREB in cancer therapy. In particular, starting with the latest CREB evidence in cancer pathophysiology, we evaluate the advancement state of CREB inhibitor design, including the histone lysine demethylases JMJD3/UTX inhibitor GSKJ4 that we newly identified as a promising CREB modulator in leukemia cells. Moreover, an accurate analysis of strengths and weaknesses is also conducted to figure out whether CREB can actually represent a therapeutic candidate or just one of the innumerable preclinical cancer targets.

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Osteosarcoma (OS) is a very aggressive metastatic pediatric and adolescent tumor. Due to its recurrent development of chemotherapy resistance, clinical outcome for OS patients remains poor. Therefore, discovering more effective anticancer agents is needed. Chlorogenic acid (CGA) is a phenolic compound contained in plant-related products that modulates many cellular functions and inhibits cell proliferation in several cancer types. However, few evidence is available in OS. Here, we investigate the effects of CGA in U2OS, Saos-2, and MG-63 OS cells. By multiple approaches, we demonstrate that CGA acts as anticancer molecule affecting the cell cycle and provoking cell growth inhibition mainly by apoptosis induction. We also provide evidence that CGA strongly activates extracellular-signal-regulated kinase1/2 (ERK1/2). Strikingly, ERK1/2 inhibitor PD98059 sensitizes the cells to CGA. Altogether, our data enforce the evidence of the anticancer activity mediated by CGA and provide the rationale for the development of innovative therapeutic strategies in OS cure.

AdipoRon (AdipoR) is the first synthetic molecule acting as a selective and potent adiponectin receptor agonist. Recently, the possible pharmacological use of AdipoR in different pathological conditions has been addressed. Interestingly, initial evidence suggests that AdipoR may have anticancer properties in different preclinical models, such as pancreatic and ovarian cancer. To our knowledge, so far no research has been directed at determining the impact of AdipoR on osteosarcoma, the most aggressive and metastatic bone malignancy occurring in childhood and adolescence age. Here, we investigate the possible antitumor effects of AdipoR in osteosarcoma cell lines. MTT and cell growth curve assays clearly indicate that AdipoR inhibits, at different extents, proliferation in both U2OS and Saos-2 osteosarcoma cell lines, the latter being more sensitive. Moreover, flow cytometry-based assays point out a significant G0/G1 phase accumulation and a contemporary S phase decrease in response to AdipoR. Consistent with the different sensitivity, a strong subG1 appearance in Saos-2 after 48 and 72 hours of treatment is also observed. The investigation of the molecular mechanisms highlights a common and initial ERK1/2 activation in response to AdipoR in both Saos-2 and U2OS cells. Interestingly, a simultaneous and dramatic downregulation of p70S6K phosphorylation, one of the main targets of mTORC1 pathway, has also been observed in AdipoR-treated Saos-2, but not in U2OS cells. Importantly, a strengthening of AdipoR-induced effects was reported upon everolimus-mediated mTORC1 perturbation in U2OS cells. In conclusion, our findings provide initial evidence of AdipoR as an anticancer molecule differently affecting various signaling pathways involved in cell cycle and cell death in osteosarcoma cells and encourage the design of future studies to further understand its pattern of activities.

Chlorogenic acid (CGA) is a very common dietary polyphenolic compound. CGA is becoming very attractive due to its potential use as preventive and therapeutic agent in many diseases, including cancer. Inorganic/organic hybrid materials are gaining considerable attention in the biomedical field. The sol-gel process provides a useful way to obtain functional organic/inorganic hybrids. The aim of this study was to synthesize silica/polyethylene glycol (PEG) hybrids with different percentages of CGA by sol-gel technique and to investigate their impact on the cancer cell proliferation. Synthesized materials have been chemically characterized through the FTIR spectroscopy and their bioactivity evaluated looking by SEM at their ability to produce a hydroxyapatite layer on their surface upon incubation with simulated body fluid (SBF). Finally, their effects on cell proliferation were studied in cell lines by direct cell number counting, MTT, flow cytometry-based cell-cycle and cell death assays, and immunoblotting experiments. Notably, we found that SiO2/PEG/CGA hybrids exhibit clear antiproliferative effects in different tumor, including breast cancer and osteosarcoma, cell lines in a CGA dependent manner, but not in normal cells. Overall, our results increase the evidence of CGA as a possible anticancer agent and illustrate the potential for clinical applications of sol-gel synthesized SiO2/PEG/CGA materials.