alexa Selective Inhibition of Lactate Influx in Cancer: An Opportunity to Augment Therapeutic Targeting | Open Access Journals
ISSN: 1948-5956
Journal of Cancer Science & Therapy
Like us on:
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

Selective Inhibition of Lactate Influx in Cancer: An Opportunity to Augment Therapeutic Targeting

Shanmugasundaram Ganapathy-Kanniappan*

Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

*Corresponding Author:
Ganapathy-Kanniappan S
Department of Radiology & Radiological Sciences
Johns Hopkins University School of Medicine
600 North Wolfe Street, Blalock 340, Baltimore, MD 21287, USA
Tel: + 410-502-6228
E-mail: [email protected]

Received Date: January 02, 2016; Accepted Date: February 15, 2016; Accepted Date: February 17, 2016

Citation: Ganapathy-Kanniappan S (2016) Selective Inhibition of Lactate Influx in Cancer: An Opportunity to Augment Therapeutic Targeting. J Cancer Sci Ther 8:036-037. doi: 10.4172/1948-5956.1000385

Copyright: © 2016 Ganapathy-Kanniappan S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Cancer Science & Therapy

Abstract

I read with great interest the article by Draoui et al., on a new class of inhibitors of lactate influx in cancer [1]. The authors report characterization of a novel compound, 7-amino carboxycoumarin (7-ACC), which specifically inhibits one of the members of monocarboxylate transporters (MCTs), the MCT-1. Using the substrate mimetic, an analog of pyruvate, the authors also demonstrate that 7-ACC selectively blocks lactate-influx and does not interfere with the uptake of the mimetic thus establishing the molecular specificity of 7-ACC in the inhibition of lactate uptake.

Short Communication

I read with great interest the article by Draoui et al., on a new class of inhibitors of lactate influx in cancer [1]. The authors report characterization of a novel compound, 7-amino carboxycoumarin (7-ACC), which specifically inhibits one of the members of monocarboxylate transporters (MCTs), the MCT-1. Using the substrate mimetic, an analog of pyruvate, the authors also demonstrate that 7-ACC selectively blocks lactate-influx and does not interfere with the uptake of the mimetic thus establishing the molecular specificity of 7-ACC in the inhibition of lactate uptake.

Recently, targeting “tumor glycolysis” or ‘aerobic glycolysis” (i.e. the process of conversion of glucose into pyruvate followed by lactate production despite oxygen availability) using energy blockers has gained renewed interest. This is primarily due to the tremendous progress in our understanding of cancer metabolism and its clinical relevance [2]. Although the glycolytic of cancers have long been known, emerging reports indicate that cancer cells exhibit metabolic plasticity [3,4]. In other words, it is increasingly evident that cancer cells possess the capacity switch to oxidative phosphorylation (OxPhos) if required, in the presence of oxygen and functionally active mitochondria. Biochemically, it implies that cancer cells may oxidize glucose into lactate (via glycolysis) or metabolize it through OxPhos pathway as may be necessary. Noteworthy, the product of tumor glycolysis (i.e.) lactate is exported via specific transporters called MCTs (which enables cancer cells to avoid intracellular acidification. Among MCTs, MCT-1 and MCT-4 have been investigated in detail due to their abundance as well as functional significance in lactate shuttle. In brief, MCT-1 imports lactate or pyruvate whereas MCT-4 exports lactate into the extracellular environment [5]. Functionally, over expression of MCT-1 enables cancer cells to import lactate from the extracellular environment (tumor microenvironment) for further utilization via acetyl CoA-pathway or mitochondrial metabolism. More importantly, the import of lactate provides cancer cells to alleviate excessive acidification of microenvironment [6]. Thus, MCT-1 as a lactate importer is indispensable for cancer cells to prevent its accumulation in tumor microenvironment. As MCTs play a pivotal role in cancer metabolism and survival, several researchers contemplated therapeutic targeting of cancer by specific MCT inhibitors. Despite encouraging results from the preclinical studies, the progress of MCT inhibitors for clinical use remains challenged, perhaps due to lack of specificity or systemic toxicity.

Since MCTs over-expression is ubiquitous in cancer, with few exceptions, the rationale to employ any anticancer therapeutic that relies on MCTs for intracellular targeting is not only feasible but also desirable. Thus, there is a growing interest in the use of small molecule inhibitors that rely on MCTs for intracellular targeting, and has been envisaged as potential anticancer strategy [7-9]. The impetus for the interest to exploit MCT-1 emanates from the biochemical phenotype of majority of cancers which show an up-regulation of MCT-1 [5]. However, one of the primary challenges for any MCT-1-dependent delivery of potential antineoplastic agent is to effectively compete with lactate (from tumor microenvironment). Such a competition with the endogenous substrate (e.g. lactate) will in turn necessitate the use of a higher dose of potential therapeutic to overcome lactate competition. Consequently, this dose-escalation has the propensity to instigate undesirable effects like systemic toxicity. In this context, if the lactate uptake is specifically blocked or markedly reduced (e.g. by 7-ACC) it would likely facilitate an increase in the cellular uptake of MCT-1-dependent anticancer agents leading to a favorable therapeutic outcome.

Intriguingly, the authors observed that despite the combinatorial approach (7-ACC and the pyruvate mimetic) the anticancer effect was similar to monotherapy (without 7-ACC) as evident by tumor size [mean (n=8)]. It is plausible that for monotherapy a maximum therapeutic dose of the mimetic was used which irrespective of the abrogation of lactate influx could promote antitumor effects. Future investigations to harness the benefits of specific inhibition of lactate influx, could use minimal therapeutic dose of potential anticancer agent (which in turn will reduce systemic toxicity) and compare between monotherapy and combinatorial approach to assess therapeutic outcome.

In cancer cells, the functional significance of MCT-4 in lactate export has long been recognized since intracellular accumulation of lactate leads to chronic acidification and cell death. However, only recently the MCT-1 dependent lactate influx has been identified as pivotal for the maintenance of tumor due to the existence of a symbiotic relationship between hypoxic and normoxic cancer cells [10]. Thus a combinatorial strategy involving the delivery of an antiglycolytic agent and an inhibitor of lactate-influx could be effective in targeting tumor energy metabolism. Although the effectiveness of this combination therapy will be relevant to cancer cells that express MCT-1, it is noteworthy that majority of tumor types have been known to up-regulate MCTs [11] suggesting that MCT-1 dependent tumor targeting in combination with specific inhibitors of lactate-influx in such malignancies could be a viable therapeutic strategy.

References

Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Relevant Topics

Article Usage

  • Total views: 7963
  • [From(publication date):
    February-2016 - Oct 24, 2017]
  • Breakdown by view type
  • HTML page views : 7900
  • PDF downloads :63
 

Post your comment

captcha   Reload  Can't read the image? click here to refresh

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

[email protected]

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

[email protected]nline.com

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001 Extn: 9042

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords