Pyrazolone-Based Zn(II) Complexes Display Antitumor Effects in Mutant p53-Carrying Cancer Cells.

The synthesis and characterization of nine Schiff bases of pyrazolone ligands ( = 1-9) and the corresponding zinc(II) complexes - of composition [Zn(L)] ( = 1-9) are reported. The molecular structures of complexes , , , , and were determined by single-crystal X-ray diffraction analysis, highlighting in all cases a distorted tetrahedral geometry around the Zn(II) ion. Density functional theory studies are performed on both the ligands and the derived complexes.

Post-Translational Modifications (PTMs) of mutp53 and Epigenetic Changes Induced by mutp53.

Wild-type (wt) p53 and mutant forms (mutp53) play a key but opposite role in carcinogenesis. wtP53 acts as an oncosuppressor, preventing oncogenic transformation, while mutp53, which loses this property, may instead favor this process. This suggests that a better understanding of the mechanisms activating wtp53 while inhibiting mutp53 may help to design more effective anti-cancer treatments.

SAHA/5-AZA Enhances Acetylation and Degradation of mutp53, Upregulates p21 and Downregulates c-Myc and BRCA-1 in Pancreatic Cancer Cells.

Epigenetic changes are common in cancer and include aberrant DNA methylation and histone modifications, including both acetylation or methylation. DNA methylation in the promoter regions and histone deacetylation are usually accompanied by gene silencing, and may lead to the suppression of tumor suppressors in cancer cells. An interaction between epigenetic pathways has been reported that could be exploited to more efficiently target aggressive cancer cells, particularly those against which current treatments usually fail, such as pancreatic cancer.

Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions.

The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment.

ATF6 supports lysosomal function in tumor cells to enable ER stress-activated macroautophagy and CMA: impact on mutant TP53 expression.

The inhibition of the unfolded protein response (UPR), which usually protects cancer cells from stress, may be exploited to potentiate the cytotoxic effect of drugs inducing ER stress. However, in this study, we found that ER stress and UPR activation by thapsigargin or tunicamycin promoted the lysosomal degradation of mutant (MUT) TP53 and that the inhibition of the UPR sensor ATF6, but not of ERN1/IRE1 or EIF2AK3/PERK, counteracted such an effect. ATF6 activation was indeed required to sustain the function of lysosomes, enabling the execution of chaperone-mediated autophagy (CMA) as well as of macroautophagy, processes involved in the degradation of MUT TP53 in stressed cancer cells.

Cancer Chemotherapy: Combination with Inhibitors (Volume I).

Cancer is one of the major causes of death globally, accounting for 10 million deaths in 2020 [...

NRF2 activation in BON‑1 neuroendocrine cancer cells reduces the cytotoxic effects of a novel Ruthenium(II)‑curcumin compound: A pilot study.

Gastroenteropancreatic neuroendocrine neoplasms (GEP‑NEN) are a group of rare tumors whose specific pathogenetic mechanisms of resistance to therapies have not been completely revealed yet. Chemotherapy is the main therapeutic approach in patients with GEP‑NEN, however, novel combination regimens and targeted therapy are continuously explored. In the present study, the anticancer effect of a novel Ruthenium (Ru)(II)‑Bisdemethoxycurcumin (Ru‑bdcurc) compound was evaluated in BON‑1 cell line, one of the few cell lines derived from GEP‑NEN, largely used in experimental research of this type of tumors.

HSP110 Inhibition in Primary Effusion Lymphoma Cells: One Molecule, Many Pro-Survival Targets.

Heat shock proteins (HSPs) are highly expressed in cancer cells and represent a promising target in anti-cancer therapy. In this study, we investigated for the first time the expression of high-molecular-weight HSP110, belonging to the HSP70 family of proteins, in Primary Effusion Lymphoma (PEL) and explored its role in their survival. This is a rare lymphoma associated with KSHV, for which an effective therapy remains to be discovered.

New Copper-Based Metallodrugs with Anti-Invasive Capacity.

While metal-based complexes are deeply investigated as anticancer chemotherapeutic drugs, fewer studies are devoted to their anti-invasive activity. Herein, two copper (Cu)(II) tropolone derivatives, [Cu(Trop)Cl] and [Cu(Trop)Sac], both containing the N,N-chelated 4,4'-bishydroxymethyl-2,2'-bipyridne ligand, were evaluated for their anticancer and anti-invasive properties. RKO (RKO-ctr) colon cancer cells and their derivatives undergoing stable small interference (si) RNA for HIPK2 protein (RKO-siHIPK2) with acquisition of pro-invasive capacity were used.

The Role of Autophagy in Brain Tumors.

Primary and metastatic brain tumors are among the most threatening diseases worldwide [...

NFE2L2 and STAT3 Converge on Common Targets to Promote Survival of Primary Lymphoma Cells.

NFE2L2 and STAT3 are key pro-survival molecules, and thus, their targeting may represent a promising anti-cancer strategy. In this study, we found that a positive feedback loop occurred between them and provided evidence that their concomitant inhibition efficiently impaired the survival of PEL cells, a rare, aggressive B cell lymphoma associated with the gammaherpesvirus KSHV and often also EBV. At the molecular level, we found that NFE2L2 and STAT3 converged in the regulation of several pro-survival molecules and in the activation of processes essential for the adaption of lymphoma cells to stress.

The Sweet Side of HIPK2.

HIPK2 is an evolutionary conserved protein kinase which modulates many molecular pathways involved in cellular functions such as apoptosis, DNA damage response, protein stability, and protein transcription. HIPK2 plays a key role in the cancer cell response to cytotoxic drugs as its deregulation impairs drug-induced cancer cell death. HIPK2 has also been involved in regulating fibrosis, angiogenesis, and neurological diseases.

NRF2 and STAT3: friends or foes in carcinogenesis?

NRF2 is a transcription factor that plays a pivotal role in carcinogenesis, also through the interaction with several pro-survival pathways. NRF2 controls the transcription of detoxification enzymes and a variety of other molecules impinging in several key biological processes. This perspective will focus on the complex interplay of NRF2 with STAT3, another transcription factor often aberrantly activated in cancer and driving tumorigenesis as well as immune suppression.

p53 Function and Dysfunction in Human Health and Diseases.

The p53 protein is a sequence-specific DNA-binding transcription factor that, in response to stressful stimuli, regulates gene expression related to multiple cellular functions including, but not limited to, cell cycle arrest, cell apoptosis, cell growth, DNA repair, cell metabolism, and the immune response [...

HIPK2 in Angiogenesis: A Promising Biomarker in Cancer Progression and in Angiogenic Diseases.

Angiogenesis is the formation of new blood capillaries taking place from preexisting functional vessels, a process that allows cells to cope with shortage of nutrients and low oxygen availability. Angiogenesis may be activated in several pathological diseases, from tumor growth and metastases formation to ischemic and inflammatory diseases. New insights into the mechanisms that regulate angiogenesis have been discovered in the last years, leading to the discovery of new therapeutic opportunities.

HIPK2 as a Novel Regulator of Fibrosis.

Fibrosis is an unmet medical problem due to a lack of evident biomarkers to help develop efficient targeted therapies. Fibrosis can affect almost every organ and eventually induce organ failure. Homeodomain-interacting protein kinase 2 (HIPK2) is a protein kinase that controls several molecular pathways involved in cell death and development and it has been extensively studied, mainly in the cancer biology field.

NRF2 and Bip Interconnection Mediates Resistance to the Organometallic Ruthenium-Cymene Bisdemethoxycurcumin Complex Cytotoxicity in Colon Cancer Cells.

Organometallic ruthenium (Ru)(II)-cymene complexes display promising pharmacological properties and might represent alternative therapeutic agents in medical applications. Polyphenols, such as curcumin and curcuminoids, display beneficial properties in medicine, including chemoprevention. Here we analyzed the anticancer effect of a cationic Ruthenium (Ru)(II)-cymene Bisdemethoxycurcumin (Ru-bdcurc) complex.

NRF2 in Cancer: Cross-Talk with Oncogenic Pathways and Involvement in Gammaherpesvirus-Driven Carcinogenesis.

Expanding knowledge of the molecular mechanisms at the basis of tumor development, especially the cross-talk between oncogenic pathways, will possibly lead to better tailoring of anticancer therapies. Nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in cancer progression, not only because of its antioxidant activity but also because it establishes cross-talk with several oncogenic pathways, including Heat Shock Factor1 (HSF1), mammalian target of rapamycin (mTOR), and mutant (mut) p53. Moreover, the involvement of NRF2 in gammaherpesvirus-driven carcinogenesis is particularly interesting.

The Impact of COVID-19 Infection in Cancer 2020-2021.

This Editorial summarizes the findings of the articles submitted in 2020 and 2021 to the Special Issue "The Impact of COVID-19 in Cancer".

c-Myc Sustains Pancreatic Cancer Cell Survival and mutp53 Stability through the Mevalonate Pathway.

It has been shown that wild-type (wt)p53 inhibits oncogene c-Myc while mutant (mut)p53 may transactivate it, with an opposite behavior that frequently occurs in the crosstalk of wt or mutp53 with molecules/pathways promoting carcinogenesis. Even if it has been reported that mutp53 sustains c-Myc, whether c-Myc could in turn influence mutp53 expression remains to be investigated. In this study, we found that pharmacological or genetic inhibition of c-Myc downregulated mutp53, impaired cell survival and increased DNA damage in pancreatic cancer cells.

ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress.

Colon cancer represents one of the most common and aggressive cancers in its advanced state. Among the most innovative anti-cancer approaches, the manipulation of UPR is a promising one, effective also against cancers carrying dysfunctional p53. Interestingly, it is emerging that UPR cross-talks with DDR and that targeting the interplay between these two adaptive responses may be exploited to overcome the resistance to the single DDR- and UPR-targeting treatments.

Interconnected Adaptive Responses: A Way Out for Cancer Cells to Avoid Cellular Demise.

Different from normal cells, cancer cells must hyperactivate a variety of integrated responses in order to survive their basal stress or its exacerbation caused by exposure to anti-cancer agents. As cancer cells become particularly dependent on these adaptive responses, namely UPR, DDR autophagy, anti-oxidant and heat shock responses, this turns out to be an Achille's heel, which allows them to be selectively killed while sparing normal unstressed cells. Better knowledge of the cross-talk between these adaptive processes and their impact on the immune system is needed to design more effective anti-cancer therapies, as reviewed in this paper.

The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study.

Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) protein is the master regulator of oxidative stress, which is at the basis of various chronic diseases including cancer. Hyperactivation of NRF2 in already established cancers can promote cell proliferation and resistance to therapies, such as in colorectal cancer (CRC), one of the most lethal and prevalent malignancies in industrialized countries with limited patient overall survival due to its escape mechanisms in both chemo- and targeted therapies. In this study, we generated stable NRF2 knockout colon cancer cells (NRF2-Cas9) to investigate the cell response to chemotherapeutic drugs with regard to p53 oncosuppressor, whose inhibition we previously showed to correlate with NRF2 pathway activation.