Starve Cancer Cells Research Articles

Identifying Potential Autophagy Modulators in Panch Phoron Spices (P5S): An In Silico approach.

Despite recent breakthroughs in diagnosis and treatment, cancer remains a worldwide health challenge with high mortality. Autophagy plays a major role in the progression and development. Starving cancer cells obtain nutrients through the upregulation of autophagy. Several compounds derived from natural sources, including animals, plants, and microorganisms, have been identified as potential novel anticancer drugs. Spices play an important role in human health and possess many medicinal properties. Our study aimed to identify potential autophagy modulators from panch phoron spices (P5S) through in silico approaches. Herein, we report a structure-based virtual screening of compounds isolated from P5S (i.e., cumin, fenugreek, fennel, black mustard, and black cumin) against the molecular targets of autophagy. Using various computational tools, we attempted to identify potential modulators of autophagy. Among all the screening results (such as binding energy, hydrogen bonding, drug-likeness, bioactivity, ADME properties, and toxicity), P5S, stigmasterol, and tigogenin showed the best drug-like properties and binding affinity toward the selected targets of autophagy. Furthermore, the stability of both complexes was evaluated by performing a 100 ns molecular dynamics simulation (MDS) using Schrodinger's Desmond Module. Our results provide insight into the efficacy of P5S components against cancer. Therefore, targeting autophagy using these molecules may be an effective and potential drug candidate for cancer treatment. In conclusion, stigmasterol and tigogenin may act as potential candidates for anticancer drugs by targeting autophagy.

Pickering emulsion with tumor vascular destruction and microenvironment modulation for transarterial embolization therapy.

In the clinic, Lipiodol chemotherapeutic emulsions remain a main choice for patients diagnosed with hepatocellular carcinoma (HCC) via the mini-invasive transarterial chemoembolization (TACE) therapy. However, the poor stability of conventional Lipiodol chemotherapeutic emulsions would result in the fast drug diffusion and incomplete embolization, inducing systemic toxicity and impairing the efficacy of TACE therapy. Therefore, it is of great importance to construct alternative formulations based on commercial Lipiodol to achieve the improved efficacy and safety of HCC treatment. Herein, calcium phosphate (CaP) nanoparticles-stabilized Lipiodol Pickering emulsion (CaP-LPE) with improved stability and pH-responsiveness is prepared and utilized for the encapsulation of combretastatin A4-phosphate (CA4P), a clinically approved vascular disrupting agent. The obtained CA4P-loaded CaP-LPE (CCaP-LPE) was shown to be enhanced stability compared to conventional Lipiodol emulsion and pH-responsive release of the encapsulated drugs. On one hand, the released CA4P could disrupt tumor vascular and cut off the blood supplying of tumor cells, thus starving cancer cells. Moreover, it was revealed that CCaP-LPE could reverse immunosuppressive tumor microenvironment (TME) by neutralizing tumor acidity, leading to the increased infiltration of CD8+ T cells and the decreased percentages of immunosuppressive cells. As the result, such CCaP-LPE could effectively shrink orthotopic N1S1 HCC tumors in rats by eliciting a potent antitumor immune response. Therefore, this study highlights a simple strategy to construct a novel LPE with the potencies of tumor vascular disruption and TME modulation, holding a great promise for TAE therapy of HCC.

Role of Intermittent Fasting In Starving Cancer Cells

Introduction. An absolute burden of over 35 million new cancer cases is predicted by 2050. Although significant progress has been made in the field of oncology via the use of surgical removal, radiation treatment, chemotherapy, and the introduction of immunotherapy, the overall rates of survival and prognoses for cancer patients are still unsatisfactory. In the last decade, intermittent fasting (IF) has become increasingly popular for weight control and potential health benefits. Additionally, research has primarily focused on investigating the impact of IF on metabolism, mitochondrial function, stress responses, repair mechanisms, and autophagy. The aim of the study. To make a literature review about the role of intermittent fasting in starving cancer cells. Materials and methods. This narrative review involved a comprehensive search through databases such as PubMed and Google Scholar. Distinct keywords such as - ″intermittent fasting″, ″intermittent fasting regimens″, ″calorie restriction″, ″oncology″, ″chemotherapy″ and ″tumor microenvironment″ were used. Results. IF exhibits significant impacts on the immune system's ability to fight against tumors by strengthening the ability of hematopoietic stem cells to replenish themselves and enhance immunosuppression. Under an IF program, certain tissues and organs exhibit enhanced resilience to various stressors. Emerging research shows that IF has the potential to enhance the effectiveness and tolerance of anticancer medicines, regulate carcinogenic influences, reprogram clock genes' rhythmic expression in tumor environments, inhibit tumor growth by modifying natural processes like insulin signalling, heme oxygenase-1, prevent the proliferation of myeloid-derived suppressor cells and priming the tumor microenvironment to support drug delivery that targets tumors. Cancer treatment via IF notably shields normal cells while raising the efficacy of chemotherapy (CT) and reducing CT-induced inflammation via several immunological, biochemical, and molecular mechanisms. Conclusions. Regularly practising fasting for more than one day may confer notable health benefits by protecting healthy normal cells against the deleterious effects of chemotherapy and radiation. The synergistic therapeutic impact of intermittent fasting alongside chemotherapy on tumors suggests that it enhances the efficacy of chemotherapy while also notably reducing chemotherapy-induced inflammation. While intermittent fasting shows promise for certain cancers, such as breast cancer, its efficacy for other types remains uncertain, necessitating further research and personalized treatment plans.

Starving cancer cells to enhances DNA damage and immunotherapy response.

Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies, including chemotherapy, radiotherapy, and hormonal treatments, often fail due to toxicities, off-target effects, and acquired resistance. This research perspective defines an alternative therapeutic strategy focusing on the metabolic vulnerabilities of PCa cells, specifically their reliance on non-essential amino acids such as cysteine. Using an engineered enzyme cyst(e)inase to deplete the cysteine/cystine can induce oxidative stress and DNA damage in cancer cells. This depletion elevates reactive oxygen species (ROS) levels, disrupts glutathione synthesis, and enhances DNA damage, leading to cancer cell death. The combinatorial use of cyst(e)inase with agents targeting antioxidant defenses, such as thioredoxins, further amplifies ROS accumulation and cytotoxicity in PCa cells. Overall, in this perspective provides a compressive overview of the previous work on manipulating amino acid metabolism and redox balance modulate the efficacy of DNA repair-targeted and immune checkpoint blockade therapies in prostate cancer.

Abstract 3080: Activation of mTORC2/Akt is amplified during glutamine starvation and is mediated by GCN2

Abstract Highly proliferative cells like cancer cells depend on glucose and glutamine to augment flux through metabolic and biosynthetic pathways. The mechanistic target of rapamycin (mTOR) integrates signals from nutrients and other growth signals to maintain metabolic homeostasis. Whereas mTOR complex 1 (mTORC1) is activated by the presence of nutrients to promote anabolic metabolism, mTORC2 is activated by nutrient fluctuations, leading to increased Akt phosphorylation at Ser473. How mTORC2 signaling can be augmented by nutrient starvation remains poorly understood. Here, we found that General Control Nonderepressible kinase 2 (GCN2), an amino acid starvation-sensing kinase, conveys glutamine depletion to mTORC2. mTORC2 enhances Akt phosphorylation and Akt feeds back to mTORC2 to augment its activity during glutamine starvation. Amino acid starvation in vivo also enhances mTORC2/Akt signaling via GCN2. Our findings reveal that manipulating the GCN2/mTORC2/Akt signaling cassette could have therapeutic benefit to more effectively starve cancer cells. Citation Format: Tatiana Hernandez, Nikhil Patel*, Jedrick Magsino, Jay Kavia, Aparna Ragupathi, Alysta Paneque, Tracy G. Anthony, Guy Werlen, Estela Jacinto. Activation of mTORC2/Akt is amplified during glutamine starvation and is mediated by GCN2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3080.

Pharmacokinetic/pharmacodynamic model of a methionine starvation based anti-cancer drug.

A new therapeutic approach against cancer is developed by the firm Erytech. This approach is based on starved cancer cells of an amino acid essential to their growth (the L-methionine). The depletion of plasma methionine level can be induced by an enzyme, the methionine-γ-lyase. The new therapeutic formulation is a suspension of erythrocytes encapsulating the activated enzyme. Our work reproduces a preclinical trial of a new anti-cancer drug with a mathematical model and numerical simulations in order to replace animal experiments and to have a deeper insight on the underlying processes. With a combination of a pharmacokinetic/pharmacodynamic model for the enzyme, substrate, and co-factor with a hybrid model for tumor, we develop a "global model" that can be calibrated to simulate different human cancer cell lines. The hybrid model includes a system of ordinary differential equations for the intracellular concentrations, partial differential equations for the concentrations of nutrients and drugs in the extracellular matrix, and individual based model for cancer cells. This model describes cell motion, division, differentiation, and death determined by the intracellular concentrations. The models are developed on the basis of experiments in mice carried out by Erytech. Parameters of the pharmacokinetics model were determined by fitting a part of experimental data on the concentration of methionine in blood. Remaining experimental protocols effectuated by Erytech were used to validate the model. The validated PK model allowed the investigation of pharmacodynamics of cell populations. Numerical simulations with the global model show cell synchronization and proliferation arrest due to treatment similar to the available experiments. Thus, computer modeling confirms a possible effect of treatment based on the decrease of methionine concentration. The main goal of the study is the development of an integrated pharmacokinetic/pharmacodynamic model for encapsulated methioninase and of a mathematical model of tumor growth/regression in order to determine the kinetics of L-methionine depletion after co-administration of Erymet product and Pyridoxine.

The applications of nanozymes in cancer therapy: based on regulating pyroptosis, ferroptosis and autophagy of tumor cells.

Nanozymes are nanomaterials with catalytic properties similar to those of natural enzymes, and they have recently been collectively identified as a class of innovative artificial enzymes. Nanozymes are widely used in various fields, such as biomedicine, due to their high catalytic activity and stability. Nanozymes can trigger changes in reactive oxygen species (ROS) levels in cells and the activation of inflammasomes, leading to the programmed cell death (PCD), including the pyroptosis, ferroptosis, and autophagy, of tumor cells. In addition, some nanozymes consume glucose, starving cancer cells and thus accelerating tumor cell death. In addition, the electric charge of the structure and the catalytic activity of nanozymes are sensitive to external factors such as light and electric and magnetic fields. Therefore, nanozymes can be used with different therapeutic methods, such as chemodynamic therapy (CDT), photodynamic therapy (PDT) and sonodynamic therapy (SDT), to achieve highly efficient antitumor effects. Many cancer therapies induce tumor cell death via the pyroptosis, ferroptosis, and autophagy of tumor cells mediated by nanozymes. We review the mechanisms of pyroptosis, ferroptosis, and autophagy in tumor development, as well as the potential application of nanozymes to regulate pyroptosis, ferroptosis, and autophagy in tumor cells.

Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer

Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic.

Metal-free polymer nano-photosensitizer actuates ferroptosis in starved cancer

The microenvironment in solid tumors drives the fate of cancer cells to ferroptosis, yet the underlying mechanism remains incompletely understood. Herein, we report a metal-free polymer photosensitizer (BDPB) as a new type ferroptosis inducer of starved cancer cells. The polymer consists of boron difluoride dipyrromethene dye as the photosensitizing unit and diisopropyl-ethyl amine as the electron-donating unit. Ultrafast spectroscopy and electron spin resonance mechanistically revealed the prolonged charge-separation process in BDPB, enabling complex-I like one-electron transfer effect to produce O2●-. Unexpectedly, the O2●--generating BDPB nanoparticles (NPs) served to deactivate the AMPK-mTOR signaling pathway in normal-state cancer cells to initiate cell repair activity and survive low-dose phototherapy. However, for cancer cells in a starved state, BDPB NPs triggered glutathione peroxidase 4 downregulation, lipid peroxides accumulation, and death to cancer cells, which was identified as ferroptosis but not apoptosis, necroptosis, or autosis. The application of BDPB NPs sheds new light on the design of individualized ferroptosis inducers for combating cancer progression.

Abstract 3595: RMC-6291, a next-generation tri-complex KRASG12C(ON) inhibitor, outperforms KRASG12C(OFF) inhibitors in preclinical models of KRASG12C cancers

Abstract The KRASG12C mutation is found in 11% of non-small cell lung cancers, 4% of colorectal cancers, and 2% of pancreatic cancers in the U.S., and drives these cancers by shifting the cellular equilibrium of KRAS towards the GTP-bound, active state, KRASG12C(ON). The resulting increased levels of KRASG12C(ON) in turn increase signaling output to initiate and support the oncogenic state. In recent years, a class of KRASG12C(OFF) inhibitors has transformed the treatment landscape for patients with cancers bearing KRASG12C. These inhibitors work via sequestration of the GDP-bound, inactive state, KRASG12C(OFF), starving cancer cells of their oncogenic driver, KRASG12C(ON). Recent reports on the nature of resistance to KRASG12C(OFF) inhibitors suggest this class of drugs can be overcome through reactivation of KRASG12C to the ON form. Direct inhibition of KRASG12C(ON) with a first in class, potent, orally bioavailable, selective, tri-complex inhibitor RMC-6291, represents a more robust approach and presents the possibility that RMC-6291 will be a ‘best-in-class’ inhibitor of tumors harboring KRASG12C. RMC-6291 is a potent covalent inhibitor of KRASG12C(ON) that forms a tri-complex within tumor cells between KRASG12C(ON) and cyclophilin A (CypA), a highly abundant immunophilin. The assembled tri-complex prevents KRASG12C(ON) from signaling via steric blockade of RAS effector binding. In cells, kinetic analyses demonstrate near-immediate disruption of RAS effector binding and extinction of KRASG12C(ON) signaling. Oral administration of RMC-6291 produces deep and durable suppression of RAS pathway activity in KRASG12C tumor models and drives profound tumor regressions in vivo at well-tolerated doses. In a mouse clinical trial consisting of multiple patient- and cell line-derived xenograft models of KRASG12C NSCLC, RMC-6291 outperformed adagrasib, a KRASG12C(OFF) inhibitor, by increasing the number of responses, the depth of tumor regressions, and the durability of responses. Combination treatment with RMC-6291 and SHP2 or SOS1 inhibitors was well tolerated in preclinical models and further increased anti-tumor activity, likely by preventing reactivation of wild-type RAS proteins that cooperate with KRASG12C to fuel cancer growth. RMC-6291 also combined well with immune checkpoint inhibitors, sensitizing KRASG12C-bearing cancer models to anti-tumor immunity. RMC-6291 is a next-generation, mutant-selective inhibitor of KRASG12C(ON) that overcomes limitations of first-generation KRASG12C(OFF) inhibitors in preclinical models by directly targeting the active form of this important oncogenic driver. Citation Format: Robert J. Nichols, Y.C. Yang, Jim Cregg, Chris J. Schulze, Zhican Wang, Richa Dua, Jingjing Jiang, Lindsay S. Garrenton, Nicole Nasholm, Alun Bermingham, John E. Knox, Kyle Seamon, Michael Longhi, Kang-Jye Chou, Shaoling Li, David P. Wildes, Mallika Singh, Elena S. Koltun, Adrian L. Gill, Jacqueline A.M. Smith. RMC-6291, a next-generation tri-complex KRASG12C(ON) inhibitor, outperforms KRASG12C(OFF) inhibitors in preclinical models of KRASG12C cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3595.

Methionine Restriction: Ready for Prime Time in the Cancer Clinic?

Attempts to selectively starve cancers in the clinic have been made at least since the time of Warburg beginning 100 years ago. Calorie-restriction or low-carbohydrate diets have had limited success with cancer patients. Methionine restriction is another strategy to selectively starve cancer cells, since cancers are addicted to methionine, unlike normal cells. Methionine addiction of cancer is termed the Hoffman effect. Numerous preclinical studies over the past half century have shown methionine restriction to be highly effective against all major cancer types and synergistic with chemotherapy. Low-methionine medical diets can be effective in lowering methionine and have shown some clinical promise, but they are not palatable and thereby not sustainable. However, selectively choosing among plant-based foods allows a variety of low-methionine diets that are sustainable. Our laboratory has developed a methioninase that can be administered orally as a supplement and has resulted in anecdotal positive results in patients with advanced cancer, including hormone-independent prostate cancer, and other recalcitrant cancers. The question is whether methionine restriction through a low-methionine diet, or even greater methionine restriction with methioninase in combination with a low-methionine diet, is ready for prime time in the clinic, especially in combination with other synergistic therapy. The question will hopefully be answered in the near future, especially for advanced cancer patients who have failed all standard therapy.

Ribosome distribution affects stalling in amino-acid starved cancer cells

Protein synthesis is a process central to all life on Earth, including mammalian cells. During this process, ribosomes attach to mRNA strands and translate them into proteins using amino acids. Under stress (for example, when the supply of circulating amino acids has been disrupted by tissue injury), ribosomes can stall. Ribosome profiling, a technique that creates a snapshot of active ribosomes in a cell by sequencing ribosome-protected mRNA fragments, captures a snapshot of ribosomes along transcripts and can detect such stalling events. This method has also revealed that the patterns of ribosomes along transcripts can vary from transcript to transcript in a manner that has not yet been explained. Here, we analyzed ribosome profiling data from amino acid-starved pancreatic cancer cells to explore whether the pattern of ribosome distribution along transcripts under normal conditions can predict the degree of ribosome stalling under stress. We hypothesized that ribosomes would stall more along “elongation-limited” transcripts that have fewer ribosome footprints near the start and stop codons than “initiation-limited” transcripts that have a large fraction of footprints at the start codon. Indeed, we found that ribosomes in amino acid-deprived cells stalled more along elongation-limited transcripts. By contrast, we observed no relationship between read density near start and stop and disparities between mRNA sequencing reads and ribosome profiling reads. This research identifies an important relationship between read distribution and propensity for ribosomes to stall, although more work is needed to fully understand the patterns of ribosome distribution along transcripts in ribosome profiling data.

Surface functionalized biomimetic bioreactors enable the targeted starvation-chemotherapy to glioma

Altering the glucose supply and the metabolic pathways would be an intriguing strategy in starvation therapy toward cancers. Nevertheless, starvation therapy alone could be inadequate to eliminate tumor cells completely. Herein, a multifunctional bioreactor was fabricated for synergistic starvation-chemotherapy through embedding glucose oxidase (GOx) and doxorubicin (DOX) in the tumor targeting ligands (RGD) modified red blood cell membrane camouflaged metal-organic framework (MOF) nanoparticle (denoted as RGD-mGZD). Owing to the remarkable biointerfacing property, the designed RGD-mGZD could not only possess enhanced blood retention time inherited from red blood cells, but also preferentially target the tumor site after the modification with RGD peptide. Once the bioreactor reached the desired region, GOx promptly consumed the intratumoral glucose and oxygen to starve cancer cells for robust starvation therapy. More importantly, the aggravated acidic microenvironment at the tumor region was found to induce the decomposition of the MOF structure, thus triggering the release of DOX for reinforced chemotherapy. This bioreactor would further prompt the development of synergistic patterns toward cancer treatment in a spatiotemporally controlled manner.

PCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells

Cancer cells frequently lack nutrients like glucose, due to insufficient vascular networks. Mitochondrial phosphoenolpyruvate carboxykinase, PCK2, has recently been found to mediate partial gluconeogenesis and hence anabolic metabolism in glucose starved cancer cells. Here we show that PCK2 acts as a regulator of mitochondrial respiration and maintains the redox balance in nutrient-deprived human lung cancer cells. PCK2 silencing increased the abundance and interconversion of tricarboxylic acid (TCA) cycle intermediates, augmented mitochondrial respiration and enhanced glutathione oxidation under glucose and serum starvation, in a PCK2 re-expression reversible manner. Moreover, enhancing the TCA cycle by PCK2 inhibition severely reduced colony formation of lung cancer cells under starvation. As a conclusion, PCK2 contributes to maintaining a reduced glutathione pool in starved cancer cells besides mediating the biosynthesis of gluconeogenic/glycolytic intermediates. The study sheds light on adaptive responses in cancer cells to nutrient deprivation and shows that PCK2 confers protection against respiration-induced oxidative stress.

The Potential Health Benefits of the Ketogenic Diet: A Narrative Review.

Considering the lack of a comprehensive, multi-faceted overview of the ketogenic diet (KD) in relation to health issues, we compiled the evidence related to the use of the ketogenic diet in relation to its impact on the microbiome, the epigenome, diabetes, weight loss, cardiovascular health, and cancer. The KD diet could potentially increase genetic diversity of the microbiome and increase the ratio of Bacteroidetes to Firmicutes. The epigenome might be positively affected by the KD since it creates a signaling molecule known as β-hydroxybutyrate (BHB). KD has helped patients with diabetes reduce their HbA1c and reduce the need for insulin. There is evidence to suggest that a KD can help with weight loss, visceral adiposity, and appetite control. The evidence also suggests that eating a high-fat diet improves lipid profiles by lowering low-density lipoprotein (LDL), increasing high-density lipoprotein (HDL), and lowering triglycerides (TG). Due to the Warburg effect, the KD is used as an adjuvant treatment to starve cancer cells, making them more vulnerable to chemotherapy and radiation. The potential positive impacts of a KD on each of these areas warrant further analysis, improved studies, and well-designed randomized controlled trials to further illuminate the therapeutic possibilities provided by this dietary intervention.

Total Cellular ATP Production Changes With Primary Substrate in MCF7 Breast Cancer Cells.

Cancer growth is predicted to require substantial rates of substrate catabolism and ATP turnover to drive unrestricted biosynthesis and cell growth. While substrate limitation can dramatically alter cell behavior, the effects of substrate limitation on total cellular ATP production rate is poorly understood. Here, we show that MCF7 breast cancer cells, given different combinations of the common cell culture substrates glucose, glutamine, and pyruvate, display ATP production rates 1.6-fold higher than when cells are limited to each individual substrate. This increase occurred mainly through faster oxidative ATP production, with little to no increase in glycolytic ATP production. In comparison, non-transformed C2C12 myoblast cells show no change in ATP production rate when substrates are limited. In MCF7 cells, glutamine allows unexpected access to oxidative capacity that pyruvate, also a strictly oxidized substrate, does not. Pyruvate, when added with other exogenous substrates, increases substrate-driven oxidative ATP production, by increasing both ATP supply and demand. Overall, we find that MCF7 cells are highly flexible with respect to maintaining total cellular ATP production under different substrate-limited conditions, over an acute (within minutes) timeframe that is unlikely to result from more protracted (hours or more) transcription-driven changes to metabolic enzyme expression. The near-identical ATP production rates maintained by MCF7 and C2C12 cells given single substrates reveal a potential difficulty in using substrate limitation to selectively starve cancer cells of ATP. In contrast, the higher ATP production rate conferred by mixed substrates in MCF7 cells remains a potentially exploitable difference.

Engineering of a Core–Shell Nanoplatform to Overcome Multidrug Resistance via ATP Deprivation

Inhibiting the function of P-glycoprotein (P-gp) transporter, which causes drug efflux through adenosine triphosphate (ATP)-dependent manner, has become an effective strategy to conquer multidrug resistance (MDR) of cancer cells. However, there remains challenges for effective co-delivery, sequential release of P-gp modulator and chemotherapeutic agent. In this work, a novel type of core-shell nanoparticle is reported. It can independently encapsulate a high amount (about 683µg mg-1 ) of chemotherapeutic agent doxorubicin (DOX) in the mesoporous polydopamine (MPDA) core and glucose oxidase (GOx) in the zeolite imidazolate frameworks-8 (ZIF-8) shell, namely MPDA@ZIF-8/DOX+GOx. The fast release of GOx triggered by acid-sensitive degradation of the ZIF-8 shell consumes glucose to starve cancer cells for ATP deprivation and effectivesuppress ATP-dependent drug efflux in advance, and then effectively facilitates the accumulation of DOX in MCF-7/ADR cancer cells. Experiments in vitro and in vivo demonstrate that the fabricated nanosystem can dramatically improve anticancer effects for MDR through sequential release property and exhibit excellent biocompatibility. Overall, this work reveals new insights in the use of GOx for MDR treatment.

Mesoporous Silica-Coated Silver Nanoframes as Drug-Delivery Vehicles for Chemo/Starvation/Metal Ion Multimodality Therapy.

Cutting off the energy supply by glucose oxidase (GOx) to starve cancer cells has been a feasible and efficient oncotherapy strategy. The employment of GOx can effectively starve tumor cells by aerobic hydrolysis of glucose hopefully strengthening the abnormality (including the decrease in pH, the increase of hypoxia, and toxic hydrogen peroxide) in the tumor microenvironment (TME). On this basis, we designed and fabricated a GOx-conjugated yolk-shell Ag@mSiO2 nanoframe with Ag NPs and GOx-conjugated mesoporous silica as the yolk and the shell, respectively, to make full use of changes the GOx induces in TME. Specifically, lower pH and H2O2 could accelerate the transformation of Ag nanoparticles to poisonous Ag ions. At the same time, the anabatic hypoxia condition in turn activated chemotherapy drug tirapazamine (TPZ) to exert a chemotherapeutic effect, thereby achieving effective chemo/starvation and metal ion multimodality therapy. The drug release experiment in vitro demonstrated that the GOx is the key to the nanocarriers, which can activate the whole system. The excellent cellular uptake performances of nanocarriers were corroborated by a confocal laser scanning microscope (CLSM). In addition, its superb cancer-killing effect has been confirmed by cytotoxicity and apoptosis experiments. These results indicated that the drug-delivery system achieved the cascade cancer-killing process in situ and synergistic chemo/starvation/metal ion therapy, which has a bright prospect for treating cancer.

Natural Products and Derivatives Targeting at Cancer Energy Metabolism: A Potential Treatment Strategy.

In the 1920s, Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells. Tumor cells mainly adopt the glycolysis as energy source to maintain tumor cell growth and biosynthesis under aerobic conditions. Investigation on energy metabolism pathway in cancer cells has aroused the interest of cancer researchers all around the world. In recent years, plentiful studies suggest that targeting the peculiar cancer energy metabolic pathways, including glycolysis, mitochondrial respiration, amino acid metabolism, and fatty acid oxidation may be an effective strategy to starve cancer cells by blocking essential nutrients. Natural products (NPs) are considered as the "treasure trove of small molecules drugs" and have played an extremely remarkable role in the discovery and development of anticancer drugs. And numerous NPs have been reported to act on cancer energy metabolism targets. Herein, a comprehensive overview about cancer energy metabolism targets and their natural-occurring inhibitors is prepared.

Synthetic Sphingolipids with 1,2-Pyridazine Appendages Improve Antiproliferative Activity in Human Cancer Cell Lines.

A synthetic sphingolipid related to a ring-constrained hydroxymethyl pyrrolidine analog of FTY720 that was known to starve cancer cells to death was chemically modified to include a series of alkoxy-tethered 3,6-substituted 1,2-pyridazines. These derivatives exhibited excellent antiproliferative activity against eight human cancer cell lines from four different cancer types. A 2.5- to 9-fold reduction in IC50 in these cell lines was observed relative to the lead compound, which lacked the appended heterocycle.