Abstract
Despite advances in personalised medicine and the emerging role of immune checkpoints in directing treatment decisions in subsets of lung cancer patients, non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related deaths worldwide. The development of drug resistance plays a key role in the relapse of lung cancer patients in the clinical setting, mainly due to the unlimited renewal capacity of residual cancer stem cells (CSCs) within the tumour cell population during chemotherapy. In this study, we investigated the function of the CSC marker, aldehyde dehydrogenase (ALDH1) in retinoic acid cell signalling using an in vitro model of cisplatin resistant NSCLC. The addition of key components in retinoic acid cell signalling, all-trans retinoic acid (ATRA) and retinol to cisplatin chemotherapy, significantly reduced ALDH1-positive cell subsets in cisplatin resistant NSCLC cells relative to their sensitive counterparts resulting in the re-sensitisation of chemo-resistant cells to the cytotoxic effects of cisplatin. Furthermore, combination of ATRA or retinol with cisplatin significantly inhibited cell proliferation, colony formation and increased cisplatin-induced apoptosis. This increase in apoptosis may, at least in part, be due to differential gene expression of the retinoic acid (RARα/β) and retinoid X (RXRα) nuclear receptors in cisplatin-resistant lung cancer cells. These data support the concept of exploiting the retinoic acid signalling cascade as a novel strategy in targeting subsets of CSCs in cisplatin resistant lung tumours.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide, where non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers
This may be due to a greater inherent resistance in these cells. These observations reflect, at least in part, that observed in the clinical setting where advanced stage NSCLC patients treated with cisplatin-doublet chemotherapy eventually relapse during treatment due to acquired resistance to this platinum drug. These findings are further supported by peak plasma concentrations of cisplatin (3–5μg/ml) following intravenous infusion in lung cancer patients, which are equivalent to 10-15μM cisplatin in vitro
Cancer stem cells have been described in many solid tumour types and have been characterised by their potential to survive chemotherapy treatment, initiate and maintain tumour growth, give rise to heterogeneous lineages via self-renewal and differentiation in addition to their high expression of stem cell-associated genes [41,42]
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide, where non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. The cancer stem cell (CSC) hypothesis has become a focus of platinum-induced resistance where a resilient drug-surviving subpopulation of cells endures This surviving population in turn, has been associated with relapse following initial cytotoxic therapy [11,12,13]. Recent studies have shown that inhibition of individual stemness markers such as Nanog, Oct-4 or Sox-2 in NSCLC CSCs, decreases self-renewal and tumour initiation capabilities and promotes chemotherapeutic sensitivity This highlights the clinical potential of targeting CSCs to re-sensitise drug resistant tumour cells to chemotherapy [32,33,34]. Cell lines, the in vitro re-sensitising capacity of retinoic acid exploitation was assessed across multiple functional parameters, including its effect on the presence of the ALDH1+ve CSC population in cisplatin-resistant lung cancer
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