Abstract
Prognosis of HPV negative head and neck squamous cell carcinoma (HNSCC) patients remains poor despite surgical and medical advances and inadequacy of predictive and prognostic biomarkers in this type of cancer highlights one of the challenges to successful therapy. Statins, widely used for the treatment of hyperlipidaemia, have been shown to possess anti-tumour effects which were partly attributed to their ability to interfere with metabolic pathways essential in the survival of cancer cells. Here, we have investigated the effect of statins on the metabolic modulation of HNSCC cancers with a vision to predict a personalised anticancer therapy. Although, treatment of tumour-bearing mice with simvastatin did not affect tumour growth, pre-treatment for 2 weeks prior to tumour injection, inhibited tumour growth resulting in strongly increased survival. This was associated with increased expression of the monocarboxylate transporter 1 (MCT1) and a significant reduction in tumour lactate content, suggesting a possible reliance of these tumours on oxidative phosphorylation for survival. Since MCT1 is responsible for the uptake of mitochondrial fuels into the cells, we reasoned that inhibiting it would be beneficial. Interestingly, combination of simvastatin with AZD3965 (MCT1 inhibitor) led to further tumour growth delay as compared to monotherapies, without signs of toxicity. In clinical biopsies, prediagnostic statin therapy was associated with a significantly higher MCT1 expression and was not of prognostic value following conventional chemo-radiotherapy. These findings provide a rationale to investigate the clinical effectiveness of MCT1 inhibition in patients with HNSCC who have been taking lipophilic statins prior to diagnosis.
Highlights
Statins are structural analogues of mevalonate and act via inhibition of the 3-hydroxymethyl-3-glutaryl (HMG)-coenzyme A (CoA) reductase to competitively block the conversion of HMG-CoA to mevalonate, a precursor in the synthesis of cholesterol[1]
This is in agreement with previous findings in a panel of breast cancer cells, where it was suggested that lack of toxicity is due to pravastatin’s hydrophilic nature which prevents it from efficiently permeating cell membranes[17]
Some stated that the use of statins was associated with a significant reduction in overall cancer incidence as well as cancer-related deaths[6,31], while others found no association between statin use and mortality from or incidence of cancer[32]
Summary
Statins are structural analogues of mevalonate and act via inhibition of the 3-hydroxymethyl-3-glutaryl (HMG)-coenzyme A (CoA) reductase to competitively block the conversion of HMG-CoA to mevalonate, a precursor in the synthesis of cholesterol[1]. MCTs are a family of transmembrane proteins that mediate the transport of monocarboxylates such as pyruvate and lactate, with MCT1 and MCT4 being the main ones implicated in cancer[11] The aim of this project was to investigate potential statin-induced metabolic modulation in head and neck squamous cell carcinoma (HNSCC) with particular emphasis on the expression of MCT1 and MCT4 and whether statin use could be of predictive value in designing a personalised anti-cancer therapy. This is important since, with the exception of HPV infection, there is a lack of predictive and prognostic biomarkers in this type of cancer[12]. There is an urgent need to develop more effective therapies for this deadly disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
