Lone Target
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As tumour cells re-programme metabolic pathways to support their growth, these tumour cell-specific pathways offer novel drug targets for cancer therapy. The logic is simple: counter the re-programmed metabolic pathways to negate their tumour-promoting advantages. In theory, this can be done by blocking glycolysis, inhibiting LDH or preventing lactic acid efflux via MCTs. Indeed, all of these avenues are actively being pursued as potential targets for cancer therapy in the design of new anti-cancer drugs. Lonidamine [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid] represents one such drug; it is approved in many European countries for cancer treatment and has been shown to improve the efficacy of other chemotherapy agents when used in combination [14,15]. In the United States, the drug was evaluated in a phase 3 clinical trial for the treatment of benign prostatic hyperplasia, but the Food and Drug Administration has suspended the trial due to development of liver toxicity in some patients on the drug. However, other clinical trials to determine the efficacy of lonidamine for different solid tumours are still ongoing. Investigations into the molecular mechanisms of the anti-cancer effects of lonidamine have revealed that the drug is an inhibitor of the glycolytic enzyme hexokinase II (HKII) [16]. There are four isoforms of hexokinase, and HKII is selectively up-regulated in tumours [17]. In addition, this isoform is bound to the outer membrane of the mitochondrion where it is physically associated with the mitochondrial permeability transition pore, which consists of the adenine nucleotide translocase (ANT) in the inner mitochondrial membrane (IMM) and the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane (OMM) [18,19]. The interaction of the enzyme with the permeability pore occurs via VDAC. The physical proximity of HKII to the permeability pore is important to tumour cells because it allows the enzyme ready access to mitochondrial ATP via ANT. The end result of lonidamine treatment is therefore the blockade of glycolysis, thereby interfering with ATP production in tumour cells. Subsequent to the original discovery of HKII as a target, two additional targets have been identified for lonidamine: VDAC and Complex II. VDAC as a component of the mitochondrial permeability transition pore plays a critical role in the control of mitochondria-initiated apoptosis [20]. The anti-apoptotic proteins such as Bcl-2 maintain the permeability pore in a closed state, preventing the cytoplasmic release of pro-apoptotic proteins such as cytochrome c and apoptosis-inducing factor, which are normally located in the inter-membrane space of mitochondria. Lonidamine disrupts the barrier function of this permeability pore, thus triggering apoptosis [21]. Inhibition of Complex II in the electron transport chain, also known as succinate dehydrogenase (SDH), by lonidamine interferes with the citric acid cycle and also with the electron transport chain [22]. Later studies have revealed the complexity of the interaction between lonidamine and Complex II [23]; the drug blocks the transfer of electrons from succinate to Coenzyme Q but does not interfere with the conversion of succinate to fumarate.
The apparent lack of specificity for the interaction of lonidamine with its targets is intriguing. HKII catalyses the phosphorylation of glucose, VDAC is an anion channel, Complex II converts succinate to fumarate and transfers electrons to Coenzyme Q, MPC transports pyruvate but not lactate and MCT1 and MCT4 transport pyruvate as well as lactate. There is no obvious commonality among these different lonidamine targets either in terms of their biological function or in terms of their substrates. It is interesting however to note that MPC and MCTs accept monocarboxylates as substrates and that lonidamine does possess a monocarboxylate group. But we do not know yet whether lonidamine is a transportable substrate for either of these transporters. The study by Nancolas et al. [24] has only shown that lonidamine inhibits pyruvate transport mediated by MPC and lactate transport mediated by MCTs, but these findings do not address the issue of whether or not lonidamine is a transportable substrate for these transporters. The observed inhibition could be either due to competition between the monocarboxylate substrates and lonidamine for the transport process or due to the blockade of the transport process by lonidamine without itself being transported across the membrane by the transporters. Studies from our laboratory have shown that α-methyltryptophan blocks the function of the amino acid transporter SLC6A14 but is not a transportable substrate [28]. Additional studies are therefore needed to determine the mechanism of action of the drug on MPC and MCTs. About a year ago, we investigated whether lonidamine is transported via SLC5A8 (also known as SMCT1), a Na+-coupled monocarboxylate transporter. We did not find any evidence of lonidamine transport via the transporter, but we also did not examine if the drug works as a blocker of the transporter (E. Babu and V. Ganapathy, unpublished work).
Another interesting issue related to the findings of Nancolas et al. [24] is the relevance of the observed robust inhibition of MPC by lonidamine to the anti-cancer efficacy of the drug. Most tumour cells re-programme their metabolic pathways that result in defective mitochondrial metabolism of pyruvate. The major aspect of this re-programme is the tumour cell-specific up-regulation of the enzyme pyruvate dehydrogenase kinase (PDK), which phosphorylates the α-subunit of the pyruvate dehydrogenase complex and inhibits the activity of the complex [29]. Forcing the tumour cells to metabolize pyruvate by mitochondrial oxidation is effective in killing these cells. This seems to be the principal mechanism underlying the anti-cancer effects of dichloroacetate, an inhibitor of PDH kinase [30]. The ability of dichloroacetate to promote pyruvate oxidation is evident from the fact that this compound is used as a drug to treat lactic acidosis. Facilitation of pyruvate metabolism by the drug alters the equilibrium between lactate and pyruvate by promoting the LDH-mediated conversion of lactate to pyruvate, thus reducing lactate levels. The well-established anti-cancer effects of dichloroacetate and the facilitation of mitochondrial oxidation of pyruvate as the underlying mechanism raise questions as to the contribution of lonidamine-mediated inhibition of MPC to the anti-cancer efficacy of the drug. On the surface, the ability of both dichloroacetate and lonidamine to function as anti-cancer drugs seems paradoxical given their opposite effects on mitochondrial pyruvate metabolism. A possible explanation for the paradox is the heterogeneity of tumour cells within a tumour. Tumour cells within a given tumour are not biochemically homogeneous; some reside in a relatively hypoxic environment whereas some have adequate supply of oxygen. Therefore, suppression of mitochondrial oxidative function is not likely to be a universal phenomenon among the tumour cells within a tumour; it is thus plausible that dichloroacetate and lonidamine actually target different groups of tumour cells to elicit their anti-cancer effects. The ability of lonidamine to inhibit SDH does not raise similar issues. Loss-of-function mutations in SDH do cause cancer (e.g. paraganglioma, gastrointestinal stromal tumours) [31], but lonidamine inhibits the ability of the enzyme to transfer electrons to Coenzyme Q without blocking the conversion of succinate to fumarate [23]. Inactivation of SDH causes cancer most likely through cellular accumulation of the onco-metabolite succinate; lonidamine may not impact on cellular levels of this metabolite.
Is his finger that much of an issue Is he simply struggling in other ways While he never lived up to his potential with the Indianapolis Colts or the Jacksonville Jaguars, he is obviously capable of doing better than dropping more than 50 percent of his on-target passes.
Exactly. Joel knew many tricks, particularly those rarely used. In practice, when we see someone leaving such tracks we immediately know that the target was once a member of special forces or internal service units. It is a person well-trained in security and defences.
Regardless of the choice of approach, the attack is based on a specific scenario were vulnerabilities in human behavior is used. The target may be manipulated into aiding the threat actor in an unwitting way. There are several ways to utilize this.
The likelihood of helping increases when a person experiences empathy towards another human being. A threat actor may use empathy to manipulate their target. One example being walking up to a target in the reception, stressed and with tearful eyes, asking if you can borrow the printer. While asking, you show the coffee spilled over the papers needed at an important presentation you are running late to.
By performing good actions, we feel good and happy with ourselves. The behavior is self-reinforcing because it is perceived as a form of reward. I have utilized this during assignments. Targets were contacted by phone and asked if they wanted to participate in a survey aimed at improving a process in the organization. When accepting and participating in the survey the target feels satisfied about having contributed to the improvements of the process.
A positive view of human beings is another factor for helping another human being. By helping another person, it increases the probability of getting help back. The threat actor can hold up the entrance door on the ground floor for the target. They share the elevator to the office floor engaging in small talk. Once at the locked office door the target wants to return the favor by unlocking and holding up the door for the threat actor. The physical intrusion is thereby a fact. 59ce067264
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