Antitumoral activity of novel 1,4-naphthoquinone derivative involves L-type calcium channel activation in human colorectal cancer cell line

• The 1,4-naphthoquinone derivatives N2 and N4 induced cytotoxicity in HT-29 cells, more selectively than the precursor N1.
• A more potent cytotoxic effect was elicited by the N4 derivative when compared to the standard drug etoposide.
• The N4 cytotoxicity mechanism involves activation of voltage-gated L-type Ca2+ channels in HT-29 cells.

Colorectal cancer (CRC) is an important public health problem estimated as the third most commonly diagnosed cancer worldwide. Naphthoquinones are compounds present in different families of plants and interesting for medicinal chemistry due to their activities as potent inhibitors of human cancer growth. In this way, our study aimed to evaluate the cytotoxicity and selectiveness of four 2,3-triazole-1,4-naphthoquinone derivatives (N1–N4) towards the CRC cell line HT-29 and normal human cells. MTT assay showed that N1, N2, N3 and N4 elicited distinct cytotoxic potency, exhibiting EC50 values of 40.6 ± 1.0, 100.1 ± 1.0, 241.9 ± 1.2 and 101.9 ± 1.1, respectively. Later, flow cytometry in HT-29 cells loaded with propidium iodide (5 μM), indicated the ability of N4 (0.5–50 μM) to induce cell membrane damage. Additionally, calcium imaging experiments were conducted in HT-29 cells loaded with 5 μM Fluo-3/AM to assess intracellular Ca2+ (iCa2+). Our data demonstrated that N4 induces a fast and strong increase of iCa2+ in HT-29 cells, mediated by voltage-gated L-type Ca2+ channels activation. In conclusion, our study reported on the cytotoxicity and selectiveness of 1,2,3-triazol substituted 1,4-naphthoquinones towards the HT-29 CRC cell line. Furthermore, we have demonstrated the participation of voltage-gated L-type Ca2+ channels in the N4 mechanism.

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