Targeting Cancer Metabolism - Revisiting the Warburg Effects

Quangdon Tran,Hyunji Lee,Jisoo Park,Seon-Hwan Kim,Jongsun Park 한국독성학회 2016 Toxicological Research Vol.32 No.3

After more than half of century since the Warburg effect was described, this atypical metabolism has been standing true for almost every type of cancer, exhibiting higher glycolysis and lactate metabolism and defective mitochondrial ATP production. This phenomenon had attracted many scientists to the problem of elucidating the mechanism of, and reason for, this effect. Several models based on oncogenic studies have been proposed, such as the accumulation of mitochondrial gene mutations, the switch from oxidative phosphorylation respiration to glycolysis, the enhancement of lactate metabolism, and the alteration of glycolytic genes. Whether the Warburg phenomenon is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. Moreover, the exact reasons and physiological values of this peculiar metabolism in cancer remain unclear. Although there are some pharmacological compounds, such as 2-deoxy-D-glucose, dichloroacetic acid, and 3-bromopyruvate, therapeutic strategies, including diet, have been developed based on targeting the Warburg effect. In this review, we will revisit the Warburg effect to determine how much scientists currently understand about this phenomenon and how we can treat the cancer based on targeting metabolism.

Targeting Cancer Metabolism - Revisiting the Warburg Effects

Tran, Quangdon,Lee, Hyunji,Park, Jisoo,Kim, Seon-Hwan,Park, Jongsun Korean Society of ToxicologyKorea Environmental Mu 2016 Toxicological Research Vol.32 No.3

After more than half of century since the Warburg effect was described, this atypical metabolism has been standing true for almost every type of cancer, exhibiting higher glycolysis and lactate metabolism and defective mitochondrial ATP production. This phenomenon had attracted many scientists to the problem of elucidating the mechanism of, and reason for, this effect. Several models based on oncogenic studies have been proposed, such as the accumulation of mitochondrial gene mutations, the switch from oxidative phosphorylation respiration to glycolysis, the enhancement of lactate metabolism, and the alteration of glycolytic genes. Whether the Warburg phenomenon is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. Moreover, the exact reasons and physiological values of this peculiar metabolism in cancer remain unclear. Although there are some pharmacological compounds, such as 2-deoxy-D-glucose, dichloroacetic acid, and 3-bromopyruvate, therapeutic strategies, including diet, have been developed based on targeting the Warburg effect. In this review, we will revisit the Warburg effect to determine how much scientists currently understand about this phenomenon and how we can treat the cancer based on targeting metabolism.

<i>Anemone rivularis</i> inhibits pyruvate dehydrogenase kinase activity and tumor growth

Chung, Tae-Wook,Lee, Jung Hee,Choi, Hee-Jung,Park, Mi-Ju,Kim, Eun-Yeong,Han, Jung Ho,Jang, Se Bok,Lee, Syng-Ook,Lee, Sang Woo,Hang, Jin,Yi, Li Wan,Ha, Ki-Tae Elsevier 2017 Journal of Ethnopharmacology Vol.203 No.-

<P><B>Abstract</B></P> <P><B>Ethnopharmacological relevance</B></P> <P> <I>Anemone rivularis</I> Buch.-Ham. ex DC. (Ranunculaceae) have been used as a traditional remedy for treatment of inflammation and cancer. However, there is no report demonstrating experimental evidence on anti-tumor action of <I>A. rivularis</I>.</P> <P><B>Aim of study</B></P> <P>The Warburg's effect, preference of aerobic glycolysis rather than oxidative phosphorylation (OXPHOS) even in oxygen rich condition, is focused as one of major characteristics of malignant tumor. Thus, we investigated the effect of <I>A. rivularis</I> on the Pyruvate dehydrogenase (PDH) kinases (PDHKs), a major molecular targets for reducing aerobic glycolysis.</P> <P><B>Materials and methods</B></P> <P>The ethanol extract of whole plant of <I>A. rivularis</I> (ARE), fingerprinted by high performance liquid chromatography (HPLC), was applied to <I>in vitro</I> and cell-based PDHK activity assays. The effect of ARE on cell viabilities of several tumor cells was estimated by MTT assay. The expression of phosphor-PDH, PDH and PDHK1 were measured by Western blot analysis. The production of reactive oxygen species (ROS) and apoptosis was measured by fluorescence-activated cell sorting analysis, using 5-(and-6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) and Annexin V/propidium iodide (PI) staining, respectively. Mitochondrial membrane potential was examined by tetramethylrhodamine methyl ester (TMRM) staining. <I>In vivo</I> anti-tumor efficacy of ARE was estimated by means of tumor volume and weight using allograft injection of murine Lewis lung carcinoma (LLC) cells to dorsa of C57BL/6 mice.</P> <P><B>Results</B></P> <P>ARE inhibited the viabilities of several cancer cells, including MDA-MB321, K562, HT29, Hep3B, DLD-1, and LLC. ARE suppressed PDHK activity in <I>in vitro</I> kinase assay, and also inhibited aerobic glycolysis by reducing phosphorylation of PDHA in human DLD-1 colon cancer and murine LLC cells. The expression of PDHK1, a major isoform of PDHKs in cancer, was not affected by ARE treatment. Moreover, ARE increased the both ROS production and mitochondrial damage. In addition, ARE suppressed the <I>in vitro</I> tumor growth through mitochondria-mediated apoptosis. The growth rates of allograft LLC cells were also reduced by ARE treatment.</P> <P><B>Conclusions</B></P> <P>Here, we firstly report that ARE inhibits PDHK activity and growth of tumor in both <I>in vitro</I> and <I>in vivo</I> experiments. Therefore, we suggest ARE as a potential candidate for developing anti-cancer drugs.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

암특이적 대사에 대한 한의학적 연구의 현황 및 전망

정태욱,김은영,최희진,최희정,하기태,Chung, Tae-Wook,Kim, Eun-Yeong,Choi, Hee-Jin,Choi, Hee-Jung,Ha, Ki-Tae 대한암한의학회 2015 大韓癌韓醫學會誌 Vol.20 No.1

Generally, normal cells synthesize adenosine triphosphate (ATP) through oxidative phosphorylation in the mitochondria. However, they produce ATP through lactic acid fermentation on hypoxic condition. Interestingly, many cancer cells rely on aerobic glycolysis for ATP generation instead of mitochondrial oxidative phosphorylation, which is termed as "Warburg effect". According to results from recent researches on differences of cancer cell metabolism from normal cell metabolism and because chemotherapy to suppress rapidly growing cells, as a side effect of cancer treatment, can still target healthy cells, there is merit in the development of small-molecule inhibitors targeting metabolic enzymes such as pyruvate dehydrogenase kinase (PDHK), lactate dehydrogenase (LDH) and monocarboxylate transporter (MCT). For new anticancer therapy, in this review, we show recent advances in study on cancer cell metabolism and molecules targeting metabolic enzymes which are importantly associated with cancer metabolism for cancer therapy. Furthermore, we would also like to emphasize the necessity of development of molecules targeting metabolic enzymes using herbal medicines and their constituents for anticancer drugs.

Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy

Chiara Vidoni,Alessandra Ferraresi,Andrea Esposito,Chinmay Maheshwari,Danny N. Dhanasekaran,Vincenzo Mollace,Ciro Isidoro 대한암예방학회 2021 Journal of cancer prevention Vol.26 No.4

Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of the calorie intake, is gaining attention as a potential adjuvant intervention for preventing and/ or fighting cancer. Several forms of energy reduction intake, which includes caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow down cancer progression. Additionally, another anti-cancer approach being under investigation relies on the use of nutraceuticals known as “Caloric Restriction Mimetics” that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing the calorie have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient/energy intake experience improved outcomes from chemo- and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed.

Cancer cell metabolism: implications for therapeutic targets

장미란,김성수,이진화 생화학분자생물학회 2013 Experimental and molecular medicine Vol.45 No.10

Cancer cell metabolism is characterized by an enhanced uptake and utilization of glucose, a phenomenon known as the Warburg effect. The persistent activation of aerobic glycolysis in cancer cells can be linked to activation of oncogenes or loss of tumor suppressors, thereby fundamentally advancing cancer progression. In this respect, inhibition of glycolytic capacity may contribute to an anticancer effect on malignant cells. Understanding the mechanisms of aerobic glycolysis may present a new basis for cancer treatment. Accordingly, interrupting lactate fermentation and/or other cancer-promoting metabolic sites may provide a promising strategy to halt tumor development. In this review, we will discuss dysregulated and reprogrammed cancer metabolism followed by clinical relevance of the metabolic enzymes, such as hexokinase, phosphofructokinase, pyruvate kinase M2, lactate dehydrogenase, pyruvate dehydrogenase kinase and glutaminase. The proper intervention of these metabolic sites may provide a therapeutic advantage that can help overcome resistance to chemotherapy or radiotherapy.

Lactate: a multifunctional signaling molecule

( Tae-yoon Lee ) 영남대학교 의과대학 2021 Yeungnam University Journal of Medicine Vol.38 No.3

Since its discovery in 1780, lactate has long been misunderstood as a waste by-product of anaerobic glycolysis with multiple deleterious effects. Owing to the lactate shuttle concept introduced in the early 1980s, a paradigm shift began to occur. Increasing evidence indicates that lactate is a coordinator of whole-body metabolism. Lactate is not only a readily accessible fuel that is shuttled throughout the body but also a metabolic buffer that bridges glycolysis and oxidative phosphorylation between cells and intracellular compartments. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells and tissues, resulting in diverse biological consequences including decreased lipolysis, immune regulation, anti-inflammation, wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, accounting for its key role in immune modulation and maintenance of homeostasis.

Fructose in the kidney: from physiology to pathology

( Takahiko Nakagawa ),( Duk-hee Kang ) 대한신장학회 2021 Kidney Research and Clinical Practice Vol.40 No.4

The Warburg effect is a unique property of cancer cells, in which glycolysis is activated instead of mitochondrial respiration despite oxygen availability. However, recent studies found that the Warburg effect also mediates non-cancer disorders, including kidney disease. Currently, diabetes or glucose has been postulated to mediate the Warburg effect in the kidney, but it is of importance that the Warburg effect can be induced under nondiabetic conditions. Fructose is endogenously produced in several organs, including the kidney, under both physiological and pathological conditions. In the kidney, fructose is predominantly metabolized in the proximal tubules; under normal physiologic conditions, fructose is utilized as a substrate for gluconeogenesis and contributes to maintain systemic glucose concentration under starvation conditions. However, when present in excess, fructose likely becomes deleterious, possibly due in part to excessive uric acid, which is a by-product of fructose metabolism. A potential mechanism is that uric acid suppresses aconitase in the Krebs cycle and therefore reduces mitochondrial oxidation. Consequently, fructose favors glycolysis over mitochondrial respiration, a process that is similar to the Warburg effect in cancer cells. Activation of glycolysis also links to several side pathways, including the pentose phosphate pathway, hexosamine pathway, and lipid synthesis, to provide biosynthetic precursors as fuel for renal inflammation and fibrosis. We now hypothesize that fructose could be the mediator for the Warburg effect in the kidney and a potential mechanism for chronic kidney disease.

Role of MicroRNAs in the Warburg Effect and Mitochondrial Metabolism in Cancer

Jin, Li-Hui,Wei, Chen Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.17

Metabolism lies at the heart of cell biology. The metabolism of cancer cells is significantly different from that of their normal counterparts during tumorigenesis and progression. Elevated glucose metabolism is one of the hallmarks of cancer cells, even under aerobic conditions. The Warburg effect not only allows cancer cells to meet their high energy demands and supply biological materials for anabolic processes including nucleotide and lipid synthesis, but it also minimizes reactive oxygen species production in mitochondria, thereby providing a growth advantage for tumors. Indeed, the mitochondria also play a more essential role in tumor development. As information about the numorous microRNAs has emerged, the importance of metabolic phenotypes mediated by microRNAs in cancer is being increasingly emphasized. However, the consequences of dysregulation of Warburg effect and mitochondrial metabolism modulated by microRNAs in tumor initiation and progression are still largely unclear.

Dichloroacetate Inhibits the Proliferation of a Human Anaplastic Thyroid Cancer Cell Line via a p53-independent Pathway

Yam Bahadur KC(얌 바하더 케이씨),Sunil Poudel(수닐 포우델),Eon Ju Jeon(전언주),Ho Sang Shon(손호상),Sung June Byun(변승준),Nam Ho Jeoung(정남호) 한국생명과학회 2018 생명과학회지 Vol.28 No.12

Warburg 효과의 발생은 고형암에서 화학적 항암제의 내성을 발생시킨다. 따라서 호기성 해당과정과 같은 에너지 대사과정은 암 치료의 중요한 표적으로 알려져 있다. Pyruvate dehydrogenase kinase (PDK) 활성 억제물질로 알려진 dichloroacetate (DCA)는 많은 암세포에서 포도당의 호기성 해당과정을 산화적인산화 과정으로 전환시킬 수 있음이 보고되었다. 이 연구는 치료가 매우 어렵다고 알려진 인간 역분화 갑상선 암세포주인 8505C의 성장에 미치는 DCA효과를 조사하였다. DCA는 정상 갑상선 세포주의 성장에는 영향을 주지 않은 반면 8505C 세포주의 성장을 특이적으로 저해하였다. DCA의 처리에 의해 8505C 세포주는 HIF1α, PDK1, Bcl-2와 같은 항-세포자살 관련 단백질들의 발현이 감소하고, Bax와 p21과 같은 세포자살 유도 단백질과 세포주기 억제 단백질의 증가로 인하여 세포주기 정지와 세포자살 유도에 의해 성장이 억제되었다. 이런 세포의 변화는 DCA 처리에 의한 활성산소족의 생산이 증가하고, 포도당 대사가 호기성 해당과정에서 산화적인산화 과정으로 전환되었기 때문이란 것을 확인하였다. 흥미롭게도, DCA는 포도당 대사과정의 변화뿐만 아니라 sodium/iodine symporter (NIS)의 발현양도 증가시킨다는 것을 확인하였다. 이 연구의 결과로 PDK 활성 저해제는 치료하기 힘든 역분화 갑상선 암 치료제로 이용할 수 있고, 또한 역분화 갑상선 암에 대한 방사능 치료의 효능을 높일 수 있을 것으로 기대된다. Occurrence of the Warburg effect in solid tumors causes resistance to cancer chemotherapy, and targeting energy metabolisms such as aerobic glycolysis is a potential strategy for alternative treatment. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), shifts glucose metabolism from aerobic glycolysis to oxidative phosphorylation (OxPhos) in many cancers. In this study, we investigated the anticancer effect of DCA on a human anaplastic thyroid cancer (ATC) cell line, 8505C. We found that DCA selectively inhibits cell proliferation of the 8505C line but not of a normal thyroid line. In 8505C, the cell cycle was arrested at the G1/S phase with DCA treatment as a result of decreased antiapoptotic proteins such as HIF1α, PDK1, and Bcl-2 and increased proapoptotic proteins such as Bax and p21. DCA treatment enhanced the production of reactive oxygen species which consequently induced cell cycle arrest and apoptosis. Interestingly, DCA treatment not only reduced lactate production but also increased the expression of sodium-iodine symporter, indicating that it restores the OxPhos of glucose metabolism and the iodine metabolism of the ATC. Taken together, our findings suggest that PDK inhibitors such as DCA could be useful anticancer drugs for the treatment of ATC and may also be helpful in combination with chemotherapy and radiotherapy.