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. 2018 Jan;57(1):3-11.
doi: 10.1002/mc.22714. Epub 2017 Aug 28.

Combination Cisplatin and Sulforaphane Treatment Reduces Proliferation, Invasion, and Tumor Formation in Epidermal Squamous Cell Carcinoma

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Free PMC article

Combination Cisplatin and Sulforaphane Treatment Reduces Proliferation, Invasion, and Tumor Formation in Epidermal Squamous Cell Carcinoma

Candace Kerr et al. Mol Carcinog. .
Free PMC article

Abstract

Epidermal squamous cell carcinoma is an extremely common type of cancer. Early tumors can be successfully treated by surgery, but recurrent disease is aggressive and resistant to therapy. Cisplatin is often used as a treatment, but the outcome is rarely satisfactory. For this reason new strategies are required. Sulforaphane is a diet-derived cancer prevention agent that is effective in suppressing tumor growth in animal models of skin cancer. We monitored the efficacy of sulforaphane and cisplatin as a combined therapy for squamous cell carcinoma. Both agents suppress cell proliferation, growth of cancer stem cell spheroids, matrigel invasion and migration of SCC-13 and HaCaT cells, and combination treatment is more efficient. In addition, SCC-13 cell derived cancer stem cells are more responsive to these agents than non-stem cancer cells. Both agents suppress tumor formation, but enhanced suppression is observed with combined treatment. Moreover, both agents reduce the number of tumor-resident cancer stem cells. SFN treatment of cultured cells or tumors increases apoptosis and p21Cip1 level, and both agents increase tumor apoptosis. We suggest that combined therapy with sulforaphane and cisplatin is efficient in suppressing tumor formation and may be a treatment option for advanced epidermal squamous cell carcinoma.

Keywords: HaCaT; SCC-13; SFN; cancer stem cells; cisplatin; squamous cell carcinoma; sulforaphane.

Conflict of interest statement

Conflict of Interest: The authors indicate no conflict of interest

Figures

Fig. 1
Fig. 1. Impact of SFN and cisplatin on cell function
A/B SCC-13 cells, growing in monolayer culture in spheroid medium, were treated as indicated and cell number was determined at the indicated times. C/D/E/F SCC-13 cell-derived eight day pre-formed spheroids were treated with cisplatin or SFN for 0 – 3 d and spheroid number per dish was determined. G/H/I SCC-13 cells were seeded atop a layer of matrigel in a BD BioCoat chamber in the presence of the indicated agents and matrigel invaded cells were imaged and counted at 18 h. J Confluent monolayers of SCC-13 cells were uniformly wounded with a pipette tip and wound closure was monitored from 0 – 24 h. The graphical values are mean ± SEM, n = 3. The asterisks indicate a significant change compared to control, p < 0.001. The double asterisks indicate a significant reduction compare to the single treatment groups, p < 0.005.
Fig. 2
Fig. 2. SFN and cisplatin impact on tumor formation by SCC-13 spheroid-derived cells
A/B/C SCC-13 spheroid cells were injected subcutaneously into immunocompromised NSG mice and at 48 h treatment was initiated with the indicated levels of SFN and cisplatin. Treatments were selected such that the individual treatments produce a partial reduction in tumor formation. Tumor size and morphology was monitored and tumor samples were harvested a 5 wk. Mouse weight was normal for the duration of the experiment in all treatment groups. The reduced weight gain in the cisplatin/SFN group was not significant different compared to the other treatment groups. D SFN and cisplatin treatment induces tumor cell apoptosis. Tumor extracts were prepared at 5 wk for immunoblot detection of the indicated epitopes. E Tumors were harvested and cells were dispersed as single cell suspensions. Twenty thousand viable cells were seeded in spheroid growth conditions and the number of spheroids formed was monitored at 5 d. All graphical values are mean ± SEM, n = 5. The asterisks indicate a significant change compared to control, p < 0.001. The double asterisks indicate a significant reduction compare to the single treatment groups, p < 0.005.
Fig. 3
Fig. 3. Impact of SFN and cisplatin on cell function
A/B HaCaT cells, growing in monolayer culture, were treated as indicated and cell number was determined at the indicated times. C/D/E HaCaT cell-derived eight day pre-formed spheroids were treated with cisplatin or SFN for 0 – 3 d and spheroid number per dish was determined. F/G HaCaT cells were seeded atop a layer of matrigel in a BD BioCoat chamber in the presence of the indicated agents and matrigel invaded cells were imaged and counted at 18 h. H Confluent monolayers of HaCaT cells were wounded with a pipette tip and wound closure was monitored rom 0 – 24 h. The graphical values are mean ± SEM, n = 3. The asterisks indicate a significant change compared to control, p < 0.001. The double asterisks indicate a significant reduction compare to the single treatment groups, p < 0.005.
Fig. 4
Fig. 4. Impact of SFN and cisplatin treatment on apoptosis in ECS cell enriched spheroid cultures
A/B/C/D SCC-13 or HaCaT cell spheroids were grown for 5 d and then treated with SFN and/or cisplatin for 72 h before preparation of extracts for immunoblot. Similar results were observed in each of three experiments. The asterisk denotes cleaved PARP.

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