Cytotoxic Imidazolyl-Mesalazine Ester-Based Ru(II) Complexes Reduce Expression of Stemness Genes and Induce Differentiation of Oral Squamous Cell Carcinoma

Abstract

The aggressiveness and recurrence of cancer is linked to cancer stem cells (CSCs), but drugs targeting CSCs may not succeed in the clinic due to the lack of a distinct CSC subpopulation. Clinical Pt(II) drugs can increase stemness. We screened 15 Ru^II or Ir^III complexes with mesalazine or 3-aminobenzoate Schiff bases of the general formulas [Ru(p-cym)L]⁺, [Ru(p-cym)L], and [Ir(Cp*)L]⁺ (L = <b>L1</b>-<b>L9</b>) and found three complexes (<b>2</b>, <b>12</b>, and <b>13</b>) that are active against oral squamous cell carcinoma (OSCC) CSCs. There is a putative oncogenic role of transcription factors (viz. NOTCH1, SOX2, c-MYC) to enhance the stemness. Our work shows that imidazolyl-mesalazine ester-based Ru^II complexes inhibit growth of CSC-enriched OSCC 3D spheroids at low micromolar doses (2 μM). Complexes <b>2</b>, <b>12</b>, and <b>13</b> reduce stemness gene expression and induce differentiation markers (<i>Involucrin</i>, <i>CK10</i>) in OSCC 3D cultures. The imidazolyl-mesalazine ester-based Ru^II complex <b>13</b> shows the strongest effect. Downregulating c-MYC suggests that Ru^II complexes may target c-MYC-driven cancers.