International Journal of Molecular Sciences

Research

Jump to: Review

17 pages, 6915 KiB

Open AccessArticle

Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability

by Jose M Ayuso, Shujah Rehman, Mehtab Farooqui, María Virumbrales-Muñoz, Vijayasaradhi Setaluri, Melissa C Skala and David J Beebe

Int. J. Mol. Sci. 2020, 21(23), 9075; https://doi.org/10.3390/ijms21239075 - 28 Nov 2020

Cited by 15 | Viewed by 3657

Abstract

Tumor-specific metabolic adaptations offer an interesting therapeutic opportunity to selectively destroy cancer cells. However, solid tumors also present gradients of nutrients and waste products across the tumor mass, forcing tumor cells to adapt their metabolism depending on nutrient availability in the surrounding microenvironment. [...] Read more.

Tumor-specific metabolic adaptations offer an interesting therapeutic opportunity to selectively destroy cancer cells. However, solid tumors also present gradients of nutrients and waste products across the tumor mass, forcing tumor cells to adapt their metabolism depending on nutrient availability in the surrounding microenvironment. Thus, solid tumors display a heterogenous metabolic phenotype across the tumor mass, which complicates the design of effective therapies that target all the tumor populations present. In this work, we used a microfluidic device to study tumor metabolic vulnerability to several metabolic inhibitors. The microdevice included a central chamber to culture tumor cells in a three-dimensional (3D) matrix, and a lumen in one of the chamber flanks. This design created an asymmetric nutrient distribution across the central chamber, generating gradients of cell viability. The results revealed that tumor cells located in a nutrient-enriched environment showed low to no sensitivity to metabolic inhibitors targeting glycolysis, fatty acid oxidation, or oxidative phosphorylation. Conversely, when cell density inside of the model was increased, compromising nutrient supply, the addition of these metabolic inhibitors disrupted cellular redox balance and led to tumor cell death. Full article

(This article belongs to the Special Issue Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics)

► Show Figures

Graphical abstract

15 pages, 2488 KiB

Open AccessArticle

A Relatively Small Gradient of Extracellular pH Directs Migration of MDA-MB-231 Cells In Vitro

by Eiji Takahashi, Daisuke Yamaguchi and Yoshihisa Yamaoka

Int. J. Mol. Sci. 2020, 21(7), 2565; https://doi.org/10.3390/ijms21072565 - 7 Apr 2020

Cited by 9 | Viewed by 2892

Abstract

Hematogenous tumor metastasis begins with the invasion and spread of primary tumor cells in the local tissue leading to intravasation. We hypothesized that tumor cells might actively migrate toward intratumor vessels with the extracellular metabolic gradient acting as a guiding cue. Here, we [...] Read more.

Hematogenous tumor metastasis begins with the invasion and spread of primary tumor cells in the local tissue leading to intravasation. We hypothesized that tumor cells might actively migrate toward intratumor vessels with the extracellular metabolic gradient acting as a guiding cue. Here, we determined in vitro whether the extracellular gradient of pH can act as a cue for directional migration in MDA-MB-231 cells. Cell migration was determined by the wound-healing assay under gradients of extracellular pH (~0.2 units/mm) and oxygen concentration (~6% O₂/mm) that were produced by a microfluidic device, gap cover glass (GCG). Without GCG, the migration of cells was spatially homogeneous; the same number of cells migrated to the rectangular wound space from the left and right boundaries. In contrast, when GCG generated pH/O₂ gradients across the wound space, the number of cells migrating to the wound space from the boundary with higher pH/O₂ values was considerably decreased, indicating a preferential movement of cells toward the region of higher pH/O₂ in the gradient. The addition of hepes in the extracellular medium abolished both the extracellular pH gradient and the directional cell migration under GCG. We conclude that relatively small gradients of pH in the extracellular medium compared to those found in Na⁺/H⁺ exchanger-driven cell migration were sufficient to guide MDA-MB-231 cells. The directional cell migration as guided by the metabolic gradient could effectively elevate the probability of intravasation and, ultimately, hematogenous metastasis. Full article

(This article belongs to the Special Issue Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics)

► Show Figures

Figure 1

20 pages, 4576 KiB

Open AccessArticle

Protective Effects of [6]-Gingerol Against Chemical Carcinogens: Mechanistic Insights

by Veronika Furlan and Urban Bren

Int. J. Mol. Sci. 2020, 21(3), 695; https://doi.org/10.3390/ijms21030695 - 21 Jan 2020

Cited by 18 | Viewed by 3751

Abstract

[6]-Gingerol from ginger has received considerable attention as a potential cancer therapeutic agent because of its chemopreventive and chemotherapeutic effects, as well as its safety. In the current study, we examined [6]-gingerol as a natural scavenger of nine ultimate chemical carcinogens to which [...] Read more.

[6]-Gingerol from ginger has received considerable attention as a potential cancer therapeutic agent because of its chemopreventive and chemotherapeutic effects, as well as its safety. In the current study, we examined [6]-gingerol as a natural scavenger of nine ultimate chemical carcinogens to which we are frequently exposed: glycidamide, styrene oxide, aflatoxin B1 exo-8,9-epoxide, β-propiolactone, ethylene oxide, propylene oxide, 2-cyanoethylene oxide, chloroethylene oxide, and vinyl carbamate epoxide. To evaluate [6]-gingerol efficacy, we expanded our research with the examination of glutathione—the strongest natural scavenger in human cells. The corresponding activation free energies were calculated using Hartree-Fock method with three flexible basis sets and two implicit solvation models. According to our results, [6]-gingerol proves to be an extremely effective scavenger of chemical carcinogens of the epoxy type. On the other hand, with the exception of aflatoxin B1 exo-8,9-epoxide, glutathione represents a relatively poor scavenger, whose efficacy could be augmented by [6]-gingerol. Moreover, our quantum mechanical study of the alkylation reactions of chemical carcinogens with [6]-gingerol and glutathione provide valuable insights in the reaction mechanisms and the geometries of the corresponding transition states. Therefore, we strongly believe that our research forms a solid basis for further computational, experimental and clinical studies of anticarcinogenic properties of [6]-gingerol as well as for the development of novel chemoprophylactic dietary supplements. Finally, the obtained results also point to the applicability of quantum chemical methods to studies of alkylation reactions related to chemical carcinogenesis. Full article

(This article belongs to the Special Issue Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics)

► Show Figures

Graphical abstract

20 pages, 3355 KiB

Open AccessArticle

The Molecular Effects of Sulforaphane and Capsaicin on Metabolism upon Androgen and Tip60 Activation of Androgen Receptor

by Catalina Carrasco-Pozo, Kah Ni Tan, Tayner Rodriguez and Vicky M. Avery

Int. J. Mol. Sci. 2019, 20(21), 5384; https://doi.org/10.3390/ijms20215384 - 29 Oct 2019

Cited by 16 | Viewed by 3578

Abstract

Androgen receptor (AR) stimulators, such as androgen and Tip60, play a pivotal role in prostatic carcinogenesis as androgen receptor signaling is critical for the growth and transformation of the prostate gland. Moreover, androgen and Tip60 promotes HIF-1α activation, involved in metabolic reprogramming by [...] Read more.

Androgen receptor (AR) stimulators, such as androgen and Tip60, play a pivotal role in prostatic carcinogenesis as androgen receptor signaling is critical for the growth and transformation of the prostate gland. Moreover, androgen and Tip60 promotes HIF-1α activation, involved in metabolic reprogramming by increasing glycolysis, a hallmark in cancer initiation and development. In this study we evaluated the effect of androgen and Tip60 stimulus in AR pathway activation and HIF-1α stabilization, in terms of proliferation and cell metabolism in androgen-sensitive LNCaP cells. The protective role of the bioactive compounds sulforaphane and capsaicin against the effect of these stimuli leading to pro-carcinogenic features was also addressed. Sulforaphane and capsaicin decreased nuclear AR, prostate specific antigen and Bcl-XL levels, and cell proliferation induced by androgen and Tip60 in LNCaP cells. These bioactive compounds prevented the increase in glycolysis, hexokinase and pyruvate kinase activity, and reduced HIF-1α stabilization induced by androgen and Tip60 in LNCaP cells. The protective role of sulforaphane and capsaicin on prostate cancer may rely on mechanisms involving the inhibition of Tip60, AR and HIF-1α effects. Full article

(This article belongs to the Special Issue Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics)

► Show Figures

Figure 1

Review

Jump to: Research

13 pages, 1327 KiB

Open AccessReview

Targeting Redox Metabolism in Pancreatic Cancer

by Nadine Abdel Hadi, Gabriela Reyes-Castellanos and Alice Carrier

Int. J. Mol. Sci. 2021, 22(4), 1534; https://doi.org/10.3390/ijms22041534 - 3 Feb 2021

Cited by 26 | Viewed by 3796

Abstract

Cell metabolism is reprogrammed in cancer cells to meet their high bioenergetics and biosynthetic demands. This metabolic reprogramming is accompanied by alterations in redox metabolism, characterized by accumulation of reactive oxygen species (ROS). Elevated production of ROS, mostly by mitochondrial respiration, is counteracted [...] Read more.

Cell metabolism is reprogrammed in cancer cells to meet their high bioenergetics and biosynthetic demands. This metabolic reprogramming is accompanied by alterations in redox metabolism, characterized by accumulation of reactive oxygen species (ROS). Elevated production of ROS, mostly by mitochondrial respiration, is counteracted by higher production of antioxidant defenses (mainly glutathione and antioxidant enzymes). Cancer cells are adapted to a high concentration of ROS, which contributes to tumorigenesis, metastasis formation, resistance to therapy and relapse. Frequent genetic alterations observed in pancreatic ductal adenocarcinoma (PDAC) affect KRAS and p53 proteins, which have a role in ROS production and control, respectively. These observations led to the proposal of the use of antioxidants to prevent PDAC development and relapse. In this review, we focus on the therapeutic strategies to further increase ROS level to induce PDAC cell death. Combining the promotion of ROS production and inhibition of antioxidant capacity is a promising avenue for pancreatic cancer therapy in the clinic. Full article

(This article belongs to the Special Issue Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics)

► Show Figures

Figure 1

42 pages, 4320 KiB

Open AccessReview

Functionalized Graphene Oxide for Chemotherapeutic Drug Delivery and Cancer Treatment: A Promising Material in Nanomedicine

by Horrick Sharma and Somrita Mondal

Int. J. Mol. Sci. 2020, 21(17), 6280; https://doi.org/10.3390/ijms21176280 - 30 Aug 2020

Cited by 96 | Viewed by 12866

Abstract

The usage of nanomaterials for cancer treatment has been a popular research focus over the past decade. Nanomaterials, including polymeric nanomaterials, metal nanoparticles, semiconductor quantum dots, and carbon-based nanomaterials such as graphene oxide (GO), have been used for cancer cell imaging, chemotherapeutic drug [...] Read more.

The usage of nanomaterials for cancer treatment has been a popular research focus over the past decade. Nanomaterials, including polymeric nanomaterials, metal nanoparticles, semiconductor quantum dots, and carbon-based nanomaterials such as graphene oxide (GO), have been used for cancer cell imaging, chemotherapeutic drug targeting, chemotherapy, photothermal therapy, and photodynamic therapy. In this review, we discuss the concept of targeted nanoparticles in cancer therapy and summarize the in vivo biocompatibility of graphene-based nanomaterials. Specifically, we discuss in detail the chemistry and properties of GO and provide a comprehensive review of functionalized GO and GO–metal nanoparticle composites in nanomedicine involving anticancer drug delivery and cancer treatment. Full article

(This article belongs to the Special Issue Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics)

► Show Figures

Graphical abstract

28 pages, 4041 KiB

Open AccessReview

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

by Alia Ghoneum, Ammar Yasser Abdulfattah, Bailey Olivia Warren, Junjun Shu and Neveen Said

Int. J. Mol. Sci. 2020, 21(9), 3100; https://doi.org/10.3390/ijms21093100 - 28 Apr 2020

Cited by 54 | Viewed by 5808

Abstract

Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS [...] Read more.

Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir. Full article

(This article belongs to the Special Issue Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics)

► Show Figures

Figure 1

18 pages, 815 KiB

Open AccessReview

Crosstalk of lncRNA and Cellular Metabolism and Their Regulatory Mechanism in Cancer

by Yang-Hsiang Lin

Int. J. Mol. Sci. 2020, 21(8), 2947; https://doi.org/10.3390/ijms21082947 - 22 Apr 2020

Cited by 66 | Viewed by 4871

Abstract

The imbalanced regulation of metabolic homeostasis and energy production is highly associated with inflammation, tumor growth, metastasis and cancer progression. Both glycolysis and oxidative phosphorylation maintain metabolic homeostasis and energy production in cells. Long noncoding RNAs (lncRNAs) are a class of non-protein-coding transcripts [...] Read more.

The imbalanced regulation of metabolic homeostasis and energy production is highly associated with inflammation, tumor growth, metastasis and cancer progression. Both glycolysis and oxidative phosphorylation maintain metabolic homeostasis and energy production in cells. Long noncoding RNAs (lncRNAs) are a class of non-protein-coding transcripts longer than 200 nucleotides. Furthermore, lncRNAs can function as either tumor suppressors or oncogenes in cancer. Dysregulated lncRNAs reportedly regulate cancer hallmarks such as tumor growth, metabolism and metastasis. Accordingly, uncovering the interaction between lncRNAs and cellular metabolism has become a necessity when attempting to identify effective therapeutic and preventive strategies in cancer progression. This review summarizes important knowledge of the actions of known lncRNAs-mediated cancer metabolism. Full article

(This article belongs to the Special Issue Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Targeting Redox and Metabolic Mechanisms for Novel Cancer Therapeutics

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI