Larry Fliegel

Epithelial, endothelial, and many connective tissue cells are normally attached to the extracellular matrix (ECM). These cells rely on the ECM for structural support, signaling, and regulation of their behavior. When these cells lose this attachment or are in an inappropriate location, these cells soon die by a mechanism called anoikis (homelessness). Anoikis is a programmed cell death of an apoptotic nature; however, it can, in certain cases, be overcome, and detached cells can survive in the absence of the correct signals from the ECM. This is the case of malignant cells, where anoikis resistance is a prerequisite for invasion and metastasis. Without anoikis resistance (anchorage-independency), tumors would be unable to abandon their normal sites and would invade neighboring tissues and metastasize at distant locations. Anoikis is the natural barrier against cancer progression. Therefore, overcoming anoikis is a major step in cellular transformation. Cancer cells have developed many successful strategies to bypass anoikis. The main mechanism, albeit not the only one, involves hyper-activating survival pathways and over-expressing anti-apoptotic molecules. There is a strong and intertwining association between epithelial–mesenchymal transition and anoikis resistance that is discussed in depth. A better understanding of these anoikis resistance mechanisms has led to the research and development of pharmaceuticals that can counteract them.

Epithelial, endothelial and many connective tissue cells are normally attached to the extracellular matrix (ECM). These cells rely on the ECM for structural support, signaling, and regulation of their behavior. When these cells lose this attachment or are in an inappropriate location, they soon die by a mechanism called anoikis (homelessness). Anoikis, is a programmed cell death of apoptotic nature, however, in certain cases it can be overcome and detached cells can survive in the absence of the correct signals from the ECM. This is the case for malignant cells, where anoikis resistance is a prerequisite for invasion and metastasis. Without anoikis resistance (anchorage-independency), tumors would be unable to abandon their normal sites and invade neighboring tissues and metastasize at distant locations. Anoikis is the natural barrier against cancer progression. Therefore, overcoming anoikis is a major step in cellular transformation. Cancer cells have developed many successful strategies to bypass anoikis. The main mechanism, albeit not the only one, involves hyper-activating survival pathways and over-expressing anti-apoptotic molecules. There is a strong and intertwined association between epithelial mesenchymal transition and anoikis resistance that is discussed in depth. A better understanding of anoikis resistance mechanisms has led to the research and development of pharmaceuticals that can counteract them.

SOS1 is a Na⁺/H⁺ antiporter found in the plant membrane of Arabidopsis thaliana and serves as a major transporter that extrudes Na⁺ across the plasma membrane of cells in exchange for intracellular H⁺. The first 450 amino acids comprise the membrane transport domain. Using a yeast heterologous expression system, we examined nine different mutations that may either change specificity or improve salt tolerance. E261K had minor negative effects on the ability to confer tolerance to LiCl and NaCl. Mutation A399V had minor effects, lowering LiCl tolerance and slightly improving NaCl tolerance, as did the double mutant E261KA399V. Four different mutations of amino acid Y346 had varying effects. The Y346R mutation resulted in a major improvement in LiCl tolerance but did not affect NaCl tolerance. The L375I mutant showed impaired NaCl tolerance, whereas the Q362L mutant exhibited minor effects on salt tolerance. Our results demonstrate that amino acid Y346 is critical in ion selectivity and its mutation can dramatically improve LiCl salt tolerance. Other mutations showed minor improvements in the ability to confer NaCl tolerance (Y346F, A399V, and Y346A), leaving open the possibility that such mutations might improve salt tolerance in intact plant species.

SOS1 is the plant membrane Na+/H+ antiporter of Arabidopsis thaliana and is the major transporter extruding Na+ across the plasma membrane of cells in exchange for an intracellular H+. The first 450 amino acid are the membrane transport domain. We examined nine different mutations that may either change specificity or improve salt tolerance. E261K had minor negative effects on the ability to confer LiCl and NaCl tolerance. Mutation A399V had minor effects lowering LiCl tolerance and slightly improving NaCl tolerance as did the double mutant E261KA399V. Four different mutations of amino acid Y346 had varying effects. The Y346R mutation resulted in a major improvement in LiCl tolerance but did not affect NaCl tolerance. The L375I mutant was impaired in NaCl tolerance and the Q362L mutant had minor effects on salt tolerance. Our results demonstrate that amino acid Y346 is critical in ion selectivity and its mutation can dramatically improve LiCl salt tolerance. Some other mutations showed minor improvements in the ability to confer NaCl tolerance (Y346F, A399V, Y346F and Y346A) leaving open the possibility that such mutations might improve salt tolerance in intact plant species.

Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound’s in cancer is merited. Despite 50 years of experimentation, DCA’s future in therapeutics is uncertain. Without adequate clinical trials and health authorities’ approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA’s benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.

Rarely has a chemical elicited as much controversy as has dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product. Then it was a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects in experimental animals. These publications showed contradictory results in vivo and in vitro, so that a thorough consideration of this compound in cancer is merited. Despite 50 years of experimentation, DCA’s future in therapeutics is uncertain. Without adequate clinical trials and lack of health authorities’ approval, DCA has been introduced in off -label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are limited thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in oncology treatment.

Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed.

Trop-2 is a highly conserved one-pass transmembrane mammalian glycoprotein that is normally expressed in tissues such as the lung, intestines, and kidney during embryonic development. It is overexpressed in many epithelial cancers but is absent in non-epithelial tumors. Trop-2 is an intracellular calcium signal transducer that participates in the promotion of cell proliferation, migration, invasion, metastasis, and probably stemness. It also has some tumor suppressor effects. The pro-tumoral actions have been thoroughly investigated and reported. However, Trop-2’s activity in chemoresistance is less well known. We review a possible relationship between Trop-2, chemotherapy, and chemoresistance. We conclude that there is a clear role for Trop-2 in some specific chemoresistance events. On the other hand, there is no clear evidence for its participation in multidrug resistance through direct drug transport. The development of antibody conjugate drugs (ACD) centered on anti-Trop-2 monoclonal antibodies opened the gates for the treatment of some tumors resistant to classic chemotherapies. Advanced urothelial tumors and breast cancer were among the first malignancies for which these ACDs have been employed. However, there is a wide group of other tumors that may benefit from anti-Trop-2 therapy as soon as clinical trials are completed.

Rapidly proliferating cancer cells exhibit a high energy demand. However, their utilization of the glycolytic pathway is inefficient, leading to a compensatory effect wherein cancer cells consume ten to twenty times more glucose than normal cells. In cases where glucose availability is limited due to a poorly perfused hypoxic microenvironment, cancer cells resort to alternative energy sources, including fructose. Certain tumors have been found to rely heavily on fructose, and fructose utilization contributes to pro-tumoral signaling and increased cancer risk. Over the past 70 years, dietary fructose intake has steadily increased, resulting in a rise in obesity and metabolic syndrome, both of which elevate cancer risk. In this paper, we present compelling evidence that highlights the role of fructose and the glucose transporter GLUT5 in promoting specific types of tumors. We summarize the existing evidence and pathways through which fructose contributes to cancer metabolism, particularly in cases where glucose availability is restricted. Furthermore, we propose a hypothesis that elucidates the regulation of the lipogenic phenotype by dietary fructose intake and cellular energy status. It is important to note that the effects of fructose are context-dependent, with its tumor-promoting effects varying based on the energy status of the cell. We comprehensively analyze why targeting fructose uptake and fructolysis should be important for the management of some tumors and cancer prevention.