PURPOSE: R,R-1,2 cyclohexanediamine-pyrophosphato-platinum(II) (PT-112) is a novel immunogenic cell death-inducing small molecule under phase II development in several cancer types. It inhibits riboso Show more
PURPOSE: R,R-1,2 cyclohexanediamine-pyrophosphato-platinum(II) (PT-112) is a novel immunogenic cell death-inducing small molecule under phase II development in several cancer types. It inhibits ribosome biogenesis and causes organelle stresses, leading to selective immunogenic cell death in cancer cells. The possibility of PT-112's pyrophosphate moiety driving high drug concentrations to bone sites of disease has led to an interest in PT-112's use in multiple myeloma. In this study, we present findings from phase I and in vivo studies for PT-112 in relapsed or refractory multiple myeloma.
EXPERIMENTAL DESIGN: PT-112 biodistribution was analyzed in mice via laser ablation inductively coupled plasma mass spectrometry. The activity of PT-112 was assessed in de novo and transplantable Tg(Igkv3-5*-MYC)#Plbe (Vk*MYC) multiple myeloma mouse models as monotherapy or combination therapies. M-spike levels and survival were measured. A phase I dose escalation study of PT-112 monotherapy was conducted using a 3 + 3 design in patients with heavily pretreated relapsed or refractory multiple myeloma with exhausted available therapies.
RESULTS: In vivo biodistribution imaging revealed high concentrations in the bone, kidney, lung, skin, and liver. PT-112 was active in Vk*MYC multiple myeloma mouse models, both alone and in combination. Phase I data showed that PT-112 monotherapy was safe and well-tolerated, establishing a recommended phase II dose of 360 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Confirmed responses and other signals of activity were observed.
CONCLUSIONS: These results suggest a lack of cross-resistance with the standard of care and support the translational value of the Vk*MYC model system. Further clinical investigation of PT-112 is warranted in multiple myeloma. Show less
Cisplatin and oxaliplatin are Pt(II) anticancer agents that are used to treat several cancers, usually in combination with other drugs. Their efficacy is diminished by dose-limiting peripheral neuropa Show more
Cisplatin and oxaliplatin are Pt(II) anticancer agents that are used to treat several cancers, usually in combination with other drugs. Their efficacy is diminished by dose-limiting peripheral neuropathy (PN) that affects âŒ70% of patients. PN is caused by selective accumulation of the platinum drugs in the dorsal root ganglia (DRG), which overexpress transporters for cisplatin and oxaliplatin. To date, no drug is recommended for the prevention of PN. We report that Pt(IV) prodrugs of cisplatin or oxaliplatin do not induce neuropathic pain in mice, likely due to the lower accumulation of platinum in the DRG compared with Pt(II) drugs. Moreover, the multitargeting prodrug that combines cisplatin with paclitaxel, both strong inducers of PN, efficiently inhibited tumor growth in vivo without inducing neuropathic pain. The high antitumor efficacy of Pt(IV) prodrugs and their micellar counterparts and the low level of neuropathic pain associated with them make them ideal candidates for clinical use in cancer therapy. Show less
The brainâs high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformatio Show more
The brainâs high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformations, with mitochondria playing a central role in ATP production via oxidative phosphorylation. Dysregulation of this metabolic interplay is implicated in Alzheimerâs disease (AD), where compromised glucose metabolism, oxidative stress, and mitochondrial dysfunction contribute to disease progression. This review explores the intricate bioenergetic crosstalk between astrocytes and neurons, highlighting the function of mitochondrial uncoupling proteins (UCPs), particularly UCP4, as important regulators of brain metabolism and neuronal function. Predominantly expressed in the brain, UCP4 reduces the membrane potential in the inner mitochondrial membrane, thereby potentially decreasing the generation of reactive oxygen species. Furthermore, UCP4 mitigates mitochondrial calcium overload and sustains cellular ATP levels through a metabolic shift from mitochondrial respiration to glycolysis. Interestingly, the levels of the neuronal UCPs, UCP2, 4 and 5 are significantly reduced in AD brain tissue and a specific UCP4 variant has been associated to an increased risk of developing AD. Few studies modulating the expression of UCP4 in astrocytes or neurons have highlighted protective effects against neurodegeneration and aging, suggesting that pharmacological strategies aimed at activating UCPs, such as protonophoric uncouplers, hold promise for therapeutic interventions in AD and other neurodegenerative diseases. Despite significant advances, our understanding of UCPs in brain metabolism remains in its early stages, emphasizing the need for further research to unravel their biological functions in the brain and their therapeutic potential. Show less
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potenti Show more
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potential side-effects. Bioinformatic approaches, advances in machine learning techniques and the increasing deposition of high-throughput data in public databases have significantly contributed to recent advances in the field, but it is not straightforward to decide which data and methods are most suitable to use in a given case. In this review, we focus on these methods and data and their applications in generating MoA hypotheses for subsequent experimental validation. We discuss compound-specific data such as -omics, cell morphology and bioactivity data, as well as commonly used supplementary prior knowledge such as network and pathway data, and provide information on databases where this data can be accessed. In terms of methodologies, we discuss both well-established methods (connectivity mapping, pathway enrichment) as well as more developing methods (neural networks and multi-omics integration). Finally, we review case studies where the MoA of a compound was successfully suggested from computational analysis by incorporating multiple data modalities and/or methodologies. Our aim for this review is to provide researchers with insights into the benefits and drawbacks of both the data and methods in terms of level of understanding, biases and interpretation â and to highlight future avenues of investigation which we foresee will improve the field of MoA elucidation, including greater public access to -omics data and methodologies which are capable of data integration. Show less
Background Metabolic adaptations can allow cancer cells to survive DNA-damaging chemotherapy. This unmet clinical challenge is a potential vulnerability of cancer. Accordingly, there is an intense se Show more
Background Metabolic adaptations can allow cancer cells to survive DNA-damaging chemotherapy. This unmet clinical challenge is a potential vulnerability of cancer. Accordingly, there is an intense search for mechanisms that modulate cell metabolism during anti-tumor therapy. We set out to define how colorectal cancer CRC cells alter their metabolism upon DNA replication stress and whether this provides opportunities to eliminate such cells more efficiently. Methods We incubated p53-positive and p53-negative permanent CRC cells and short-term cultured primary CRC cells with the topoisomerase-1 inhibitor irinotecan and other drugs that cause DNA replication stress and consequently DNA damage. We analyzed pro-apoptotic mitochondrial membrane depolarization and cell death with flow cytometry. We evaluated cellular metabolism with immunoblotting of electron transport chain (ETC) complex subunits, analysis of mitochondrial mRNA expression by qPCR, MTT assay, measurements of oxygen consumption and reactive oxygen species (ROS), and metabolic flux analysis with the Seahorse platform. Global metabolic alterations were assessed using targeted mass spectrometric analysis of extra- and intracellular metabolites. Results Chemotherapeutics that cause DNA replication stress induce metabolic changes in p53-positive and p53-negative CRC cells. Irinotecan enhances glycolysis, oxygen consumption, mitochondrial ETC activation, and ROS production in CRC cells. This is connected to increased levels of electron transport chain complexes involving mitochondrial translation. Mass spectrometric analysis reveals global metabolic adaptations of CRC cells to irinotecan, including the glycolysis, tricarboxylic acid cycle, and pentose phosphate pathways. P53-proficient CRC cells, however, have a more active metabolism upon DNA replication stress than their p53-deficient counterparts. This metabolic switch is a vulnerability of p53-positive cells to irinotecan-induced apoptosis under glucose-restricted conditions. Conclusion Drugs that cause DNA replication stress increase the metabolism of CRC cells. Glucose restriction might improve the effectiveness of classical chemotherapy against p53-positive CRC cells. Graphical Abstract The topoisomerase-1 inhibitor irinotecan and other chemotherapeutics that cause DNA damage induce metabolic adaptations in colorectal cancer (CRC) cells irrespective of their p53 status. Irinotecan enhances the glycolysis and oxygen consumption in CRC cells to deliver energy and biomolecules necessary for DNA repair and their survival. Compared to p53-deficient cells, p53-proficient CRC cells have a more active metabolism and use their intracellular metabolites more extensively. This metabolic switch creates a vulnerability to chemotherapy under glucose-restricted conditions for p53-positive cells.
Supplementary Information The online version contains supplementary material available at 10.1186/s40170-022-00286-9. Show less
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In Show more
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 ÎŒM. The inhibitory concentrations of cell growth by 50% (IC 50 ) of oxaliplatin were 4.40â12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs. Show less
The Basis Set Exchange (BSE) has been a prominent fixture in the quantum chemistry community. First publicly available in 2007, it is recognized by both users and basis set creators as the de facto so Show more
The Basis Set Exchange (BSE) has been a prominent fixture in the quantum chemistry community. First publicly available in 2007, it is recognized by both users and basis set creators as the de facto source for information related to basis sets. This popular resource has been rewritten, utilizing modern software design and best practices. The basis set data has been separated into a stand-alone library with an accessible API, and the Web site has been updated to use the current generation of web development libraries. The general layout and workflow of the Web site is preserved, while helpful features requested by the user community have been added. Overall, this design should increase adaptability and lend itself well into the future as a dependable resource for the computational chemistry community. This article will discuss the decision to rewrite the BSE, the new architecture and design, and the new features that have been added. Show less
In this chapter several aspects of Pt(II) are highlighted that focus on the properties of Pt(II)-RNA adducts and the possibility that they influence RNA-based processes in cells. Cellular distribution Show more
In this chapter several aspects of Pt(II) are highlighted that focus on the properties of Pt(II)-RNA adducts and the possibility that they influence RNA-based processes in cells. Cellular distribution of Pt(II) complexes results in significant platination of RNA, and localization studies find Pt(II) in the nucleus, nucleolus, and a distribution of other sites in cells. Treatment with Pt(II) compounds disrupts RNA-based processes including enzymatic processing, splicing, and translation, and this disruption may be indicative of structural changes to RNA or RNA-protein complexes. Several RNA-Pt(II) adducts have been characterized in vitro by biochemical and other methods. Evidence for Pt(II) binding in non-helical regions and for Pt(II) cross-linking of internal loops has been found. Although platinated sites have been identified, there currently exists very little in the way of detailed structural characterization of RNA-Pt(II) adducts. Some insight into the details of Pt(II) coordination to RNA, especially RNA helices, can be gained from DNA model systems. Many RNA structures, however, contain complex tertiary folds and common, purine-rich structural elements that present suitable Pt(II) nucleophiles in unique arrangements which may hold the potential for novel types of platinum-RNA adducts. Future research aimed at structural characterization of platinum-RNA adducts may provide further insights into platinum-nucleic acid binding motifs, and perhaps provide a rationale for the observed inhibition by Pt(II) complexes of splicing, translation, and enzymatic processing. Show less