Broccoli extract increases drug-mediated cytotoxicity towards cancer stem cells of head and neck squamous cell carcinoma

Osama A Elkashty,Simon D Tran

doi:10.1038/s41416-020-1025-1

Abstract

BackgroundHead and neck squamous cell carcinomas (HNSCC) are malignant neoplasms with poor prognosis. Treatment-resistant cancer stem cell (CSC) is one reason for treatment failure. Considerable attention has been focused on sulforaphane (SF), a phytochemical from broccoli possessing anticancer properties. We investigated whether SF could enhance the chemotherapeutic effects of cisplatin (CIS) and 5-fluorouracil (5-FU) against HNSCC–CSCs, and its mechanisms of action.MethodsCD44+/CD271+ FACS-isolated CSCs from SCC12 and SCC38 human cell lines were treated with SF alone or combined with CIS or 5-FU. Cell viability, colony- and sphere-forming ability, apoptosis, CSC-related gene and protein expression and in vivo tumour growth were assessed. Safety of SF was tested on non-cancerous stem cells and in vivo.ResultsSF reduced HNSCC–CSC viability in a time- and dose-dependent manner. Combining SF increased the cytotoxicity of CIS twofold and 5-FU tenfold, with no effects on non-cancerous stem cell viability and functions. SF-combined treatments inhibited CSC colony and sphere formation, and tumour progression in vivo. Potential mechanisms of action included the stimulation of caspase-dependent apoptotic pathway, inhibition of SHH pathway and decreased expression of SOX2 and OCT4.ConclusionsCombining SF allowed lower doses of CIS or 5-FU while enhancing these drug cytotoxicities against HNSCC–CSCs, with minimal effects on healthy cells.

Highlights

Head and neck squamous cell carcinomas (HNSCC) are malignant neoplasms with poor prognosis
Effects of sulforaphane on the viability and proliferation in HNSCC–cancer stem cell (CSC) Fluorescence‐activated cell sorting (FACS)-isolated CSCs were exposed to different SF concentrations
SF treatment decreased the viability of HNSCC–CSCs in a dosedependent manner (Fig. 1a)

Summary

BACKGROUND

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common malignancy worldwide, represents ~6% of all cancer cases and is accounted for 580,000 new cases and over 380,000 deaths annually.[1,2,3] The current standard treatment for HNSCC is by multimodal approaches consisting of surgery, radiotherapy and/or chemotherapy.[4]. Cancer stem cells (CSCs), known as tumour-initiating cells, are a distinct cell subpopulation within the tumour.[7] When compared with the remaining tumour cells, CSCs are often more resistant to chemoradiotherapy and more tumorigenic.[8] it is of great importance to develop strategies for targeting CSCs in order to improve HNSCC treatment outcomes. Sulforaphane (SF), a phytochemical that exists in a large amount in cruciferous plants, has shown promising anti-inflammatory, antioxidant and antitumour effects.[9,10,11,12] Recent studies have proposed that SF exerts its antitumour effects through inhibiting both cell proliferation and cell- cycle mechanisms, promoting apoptosis and protecting the precancerous cells from methylation.[12,13] its effect on CSCs in HNSCC, either alone or in combination with conventional chemotherapy, remains poorly understood.[14]. Our present study was designed to investigate whether SF could be a potent agent to enhance the chemotherapy efficacy of cisplatin (CIS) and 5-fluorouracil (5-FU) on HNSCC stem cells, and to determine its mechanisms of action

METHODS

RESULTS

DISCUSSION