Review
Recent advancements in therapeutic targeting of the Warburg effect in refractory ovarian cancer: A promise towards disease remission

https://doi.org/10.1016/j.bbcan.2021.188563Get rights and content

Abstract

Epithelial ovarian cancer, the most lethal gynecological malignancy, is diagnosed at advanced stage, recurs and displays chemoresistance to standard chemotherapeutic regimen of taxane/platinum drugs. Despite development of recent therapeutic approaches including poly-ADP ribose polymerase inhibitors, this fatal disease is diagnosed at advanced stage and heralds strategies for early detection and improved treatment. Recent literature suggests that high propensity of ovarian cancer cells to consume and metabolize glucose via glycolysis even in the presence of oxygen (the ‘Warburg effect’) can significantly contribute to disease progression and chemoresistance and hence, it has been exploited as novel drug target. This review focuses on the molecular cues of aberrant glycolysis as drivers of chemo-resistance and aggressiveness of recurrent ovarian cancer. Furthermore, we discuss the status quo of small molecule inhibition of aerobic glycolysis and significance of metabolic coupling between cancer cells and tumor microenvironment as novel therapeutic interventions against this lethal pathology.

Introduction

Epithelial ovarian cancer (EOC) which comprises clear cell, mucinous, endometroid, low grade serous (LGS) and high grade serous (HGS) ovarian carcinomas, is the most lethal gynecological malignancy and is often diagnosed in advanced disease stage [1]. Among all subtypes, HGSOC accounts for >80% of all cases and these tumors are often associated with high grade nuclear atypia, hyperchromatic nuclei along with very high frequency of alterations in several genes such as TP53, MYC, BRCA1, BRCA2, CCNE1, KRAS and loss of heterozygosity (LOH) on chromosomes 7q and 9p [2]. Although the mainstay of primary management of HGSOC involves surgical debulking of the visible tumor mass followed by taxanes (paclitaxel, docetaxel etc.) and/or platinum drugs (cisplatin or carboplatin) treatment and introduction of bevacizumab to this standard chemotherapy regimen improved progression-free survival (PFS), ~60% patients relapse during or after 6 months with refractory, chemoresistant tumors [3]. Despite development of several other approaches such as poly-ADP ribose polymerase (PARP) and folate receptor α inhibitors, refractory EOC (rEOC) remains largely fatal and heralds strategies for early detection, treatment and improved PFS [4].

Metabolic reprogramming especially elevated rate of glycolysis even in the presence of oxygen (the “Warburg effect) is a hallmark of cancer (Fig. 1) and it significantly contributes to the tumor development and chemoresistance via many directions such as maintenance of acidic pH in tumor microenvironment (TME) and constant supply of NAD+/lactate as precursors to biomass synthesis [5]; hence, therapeutic strategies targeting several regulators of glycolysis including hypoxia-inducible factor 1 alpha (HIF-1α), hexokinase 2 (HK2) and PI3K/AKT/mTOR pathway by many compounds including ikarugamycin, epigallocatechin-3-gallate and 2-deoxy glucose have shown promising results in several deadly pathologies like pancreatic ductal adenocarcinoma (PDA) and colon carcinoma [[6], [7], [8]]. In line of this notion, recently researchers have put serious efforts to develop novel therapeutic approaches targeting aerobic glycolysis in rEOC. This review discusses the status quo of several small molecule inhibitors and miRNAs that can target aberrant glycolysis and improve rEOC disease management and PFS. Additionally, we discuss molecular mechanisms of drug resistance related to glycolysis and implications of metabolic coupling of tumor cells and cancer-associated fibroblasts (CAFs) in the TME, also known as the reverse Warburg effect in disease relapse and management of rEOC. (See Table 1, Table 2.)

Section snippets

rEOC drug resistance and the Warburg effect

Cancer drug resistance is a complex phenomenon which includes several genes and cross-talks between many signalling pathways and hence, understanding the molecular basis involved in chemoresistance is highly warranted to overcome disease relapse and patient mortality. Majority of rEOC tumors gain chemoresistance via several primary or acquired mechanisms such as efficient DNA repair, CCNE1 amplification and molecular subtype switching [9]. Moreover, altered drug metabolism via modulation of

miRNAs that target aberrant glycolysis in EOC

miRNAs modulate a plethora of cellular and physiological functions involved in progression of many malignancies including EOC and emerging evidence suggests that they target glycolytic regulators, inhibit elevated glucose uptake and EOC progression [65]. Using several EOC cell lines such as A2780, SKOV3 and CAOV3, Zhang et al. demonstrated that miR-338-3p targeted PKM2 and inhibited EOC cell proliferation, lactate production and tumor progression [66]. In line of this observation, in an

Small molecule inhibition of the Warburg effect in EOC

Glucose addiction, elevated rate of aerobic glycolysis and hyperproliferation are associated with tumorigenesis and drug resistance. Hence, development of compounds that target glycolytic regulators in solid tumors has great therapeutic potential against many deadly human cancers [69]. In this section, we discuss recent developments on potent, selective small molecule inhibitors as well as natural compounds targeting the Warburg effect and their therapeutic applications in rEOC (summarized in

Conclusion and future prospective

Although cancer is a heterogenous disease accompanied by accumulation of thousands of somatic and germline mutations, recent literature suggests that elevated rate of glucose uptake and high propensity of tumor cells to metabolize glucose via glycolysis even in the presence of oxygen (the “Warburg effect) is a hallmark of cancer and almost every type of cancer including epithelial ovarian cancer displays this reprogrammed glucose metabolism [97]. Therefore, several regulatory components of the

Author contributions

AR conceptualized and designed the manuscript. KT wrote the first draft of the manuscript and prepared the figs. SM and AR revised and finalized the manuscript.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgement

This work was supported by the Ramalingaswami Re-entry fellowship Grant (BT/HRD/35/02/2006), Department of Biotechnology, Govt. of India to AR.

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