Pleiotropic Anticancer Properties of Scorpion Venom Peptides: Rhopalurus princeps Venom as an Anticancer Agent.

To date, the success of conventional chemotherapy, radiotherapy, and targeted biological therapies in cancer treatment is not satisfactory. The main reasons for such outcomes rely on low target selectivity, primarily in chemo- and radiotherapy, ineffectiveness to metastatic disease, drug resistance, and severe side effects. Although immune checkpoint inhibitors may offer better clinical promise, success is still limited. Since cancer is a complex systemic disease, the need for new therapeutic modalities that can target or block several steps of cancer cell characteristics, modulate or repolarize immune cells, and are less toxic to healthy tissues is essential. Of these promising therapeutic modalities are pleiotropic natural products in which scorpion venom (SV) is an excellent example. SV consists of complex bioactive peptides that are disulfide-rich of different peptides' length, potent, stable, and exerts various multi-pharmacological actions. SV peptides also contain ion channel inhibitors. These ion channels are dysregulated and overexpressed in cancer cells, and play essential roles in cancer development and invasion, as well as depolarizing immune cells. Furthermore, SV has been found to induce cancer cell apoptosis, and inhibit cancer cells proliferation, invasion, metastasis, and angiogenesis. In the current review, we are presenting data that show the pleiotropic effect of SV against different types of human cancer as well as revealing one potential anticancer agent, Rhopalurus princeps venom. Furthermore, we are addressing what is needed to be done to translate these potential cancer therapeutics to the clinic.

[Concept analysis of preparatory grief in terminal cancer patients].

PURPOSE: The purpose of this study was to conceptualize and clarify a concept of "preparatory grief" in terminal cancer patients. METHOD: A hybrid model of concept development was applied to develop a concept of preparatory grief, which included a field study carried out in Busan, Korea. Participants of this study were 8 cancer patients. RESULTS: On the basis of our literature, research and clinical experience, the concept of preparatory grief emerged as a complex phenomenon playing an important role in five areas; physical, emotional, interpersonal, religious, and transcendental dimensions. Two new attributes were defined through a field phase; trust of the post-mortal world and a serene state of mind. Indicators reflected attitudes of sadness, worry, regret, capability to adapt and hope. The results of preparatory grief were loss of energy and interest, emotional chaos, contemplation, taciturnity and restoration. CONCLUSIONS: Differentiating among preparatory grief and other symptoms in cancer patients is essential because of therapeutic implications. Understanding preparatory grief is necessary in order to manage cancer patients for promoting quality of life so that its application may have a positive impact on the patient's life.

Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention.

Despite more than 75 years of research by some of the greatest scientists in the world to conquer cancer, the clear winner is still cancer. This is reflected particularly by liver cancer that worldwide ranks fourth in terms of mortality with survival rates of no more than 3-5%. Significantly, one of the earliest discovered hallmarks of cancer had its roots in Bioenergetics as many tumors were found in the 1920s to exhibit a high glycolytic phenotype. Although research directed at unraveling the underlying basis and significance of this phenotype comprised the focus of cancer research for almost 50 years, these efforts declined greatly from 1970 to 1990 as research into the molecular and cell biology of this disease gained center stage. Certainly, this change was necessary as the new knowledge obtained about oncogenes, gene regulation, and programmed cell death once again placed Bioenergetics in the limelight of cancer research. Thus, we now have a much better molecular understanding of the high glycolytic phenotype of many cancers, the pivotal roles that Type II hexokinase-mitochondrial interactions play in this process to promote tumor cell growth and survival, and how this new knowledge can lead to improved therapies that may ultimately turn the tide on our losing war on cancer.

Signal transduction to mitochondrial ATP synthase: evidence that PDGF-dependent phosphorylation of the delta-subunit occurs in several cell lines, involves tyrosine, and is modulated by lysophosphatidic acid.

Although signal transduction mechanisms originating from receptors on the plasma membrane and targeted to metabolic and other enzymes/proteins localized in the cytoplasm or the nucleus have been extensively studied in animal cells, few such studies have focused on the mitochondrial energy producing machinery, i.e. the electron transport chain and ATP synthase complex (F0F1). Significantly, it was shown in an earlier collaborative study that platelet-derived growth factor (PDGF), which is linked in signal transduction pathways to tyrosine kinase-dependent phosphorylations, regulates the phosphorylation of the mitochondrial ATP synthase delta subunit in cortical neurons (Zhang et. al., 1995. J. Neurochem. 65, 2812-2815). This is a particularly intriguing finding in light of more recent reports demonstrating that ATP synthases are nanomotors with a central rotor, one component of which is the delta subunit. In this report, evidence is provided that the PDGF-dependent phosphorylation of the ATP synthase delta subunit is not confined to neuronal cells but can be demonstrated also in studies with PDGF-treated NIH3T3 and kidney cells. Evidence is provided also that phosphorylation of the ATP synthase delta subunit may involve its single tyrosine residue, and that this phosphorylation is modulated when the cell based assay includes lysophosphatidic acid (LPA), a phospholipid signaling molecules. Finally, results are presented of an analysis which revealed a number of potential tyrosine phosphorylation sites on three other subunits (alpha, beta, and gamma) of the F1 (catalytic) moiety of the mitochondrial ATP synthase, thus making this important complex a most attractive target for future signal transduction studies.

Cystic fibrosis transmembrane conductance regulator: the NBF1+R (nucleotide-binding fold 1 and regulatory domain) segment acting alone catalyses a Co2+/Mn2+/Mg2+-ATPase activity markedly inhibited by both Cd2+ and the transition-state analogue orthovanadate.

Cystic fibrosis (CF) is caused by mutations in the gene encoding CFTR (cystic fibrosis transmembrane conductance regulator), a regulated anion channel and member of the ATP-binding-cassette transporter (ABC transporter) superfamily. Of CFTR's five domains, the first nucleotide-binding fold (NBF1) has been of greatest interest both because it is the major 'hotspot' for mutations that cause CF, and because it is connected to a unique regulatory domain (R). However, attempts have failed to obtain a catalytically active NBF1+R protein in the absence of a fusion partner. Here, we report that such a protein can be obtained following its overexpression in bacteria. The pure NBF1+R protein exhibits significant ATPase activity [catalytic-centre activity (turnover number) 6.7 min(-1)] and an apparent affinity for ATP ( K (m), 8.7 microM) higher than reported previously for CFTR or segments thereof. As predicted, the ATPase activity is inhibited by mutations in the Walker A motif. It is also inhibited by vanadate, a transition-state analogue. Surprisingly, however, the best divalent metal activator is Co(2+), followed by Mn(2+) and Mg(2+). In contrast, Ca(2+) is ineffective and Cd(2+) is a potent inhibitor. These novel studies, while demonstrating clearly that CFTR's NBF1+R segment can act independently as an active, vanadate-sensitive ATPase, also identify its unique cation activators and a new inhibitor, thus providing insight into the nature of its active site.