Colorectal cancer is the second most common cancer in women, the third in men, and an important cause of cancer-related mortality. Recurrence and the development of chemotherapy resistance are major hindrances for patients’ treatment. The presence of cancer stem cells with chemotherapy resistance able to generate proliferating tumor cells contributes to tumor recurrence and resistance. In addition, tumor cells can develop chemoresistance through adaptation mechanisms. In this article, cancer stem cells were isolated from HT29 and SW620 colorectal cancer cell lines. Oxaliplatin resistance was induced by a single drug treatment simulating the usual guidelines of patient treatment. A comparison of these two populations showed similarities since cancer stem cells presented increased oxaliplatin resistance, and resistant cells contained an increased number of cancer stem cells. Cancer stem cells isolated from resistant cells showed increased oxaliplatin resistance. Cell invasion capacity and epithelial-mesenchymal transition were increased both in cancer stem cells and oxaliplatin-resistant cells. mRNA expression analysis showed that both cell types shared a significant proportion of commonly regulated genes. In summary, the data presented indicate that colorectal cancer stem cells and oxaliplatin-resistant cells are highly related cell populations that might have interesting implications in the development of tumor recurrence and resistance to chemotherapy.

Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyzed and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines by 1-million microarray-based comparative genomic hybridization (array-CGH) and qRT-PCR methodologies. RNA-sequencing, functional transfection assays, and gene-pathway activity analysis were used to identify genes with a potential role in the development of this malignancy. The results were further explored in 55 lung and ovarian primary tumors and control samples, and in two extensive in silico databases. Long-term cell exposure to platinum induces the frequent deletion of ITF2 gene. Its expression re-sensitized tumor cells to platinum and recovered the levels of Wnt/β-catenin transcriptional activity. ITF2 expression was also frequently downregulated in epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation between ITF2 and HOXD9 expression, revealing that Non-small cell lung cancer (NSCLC) patients with lower expression of HOXD9 had a better overall survival rate. We defined the implication of ITF2 as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. This data highlights the possible role of ITF2 and HOXD9 as novel therapeutic targets for platinum resistant tumors.

This work reports the synthesis, characterization and in vitro evaluation of three organometallic triorganotin(IV) complexes bearing a dicarbamido-bis-organosilane benzoate ligand as potential anticancer agents against colorectal cancer cells. The complexes, Sn(IV)-biSi-1, Sn(IV)-biSi-2 and Sn(IV)-biSi-3, differ in the alkyl groups directly bound to the Sn(IV) center (methyl, n-propyl and isopropyl, respectively). Their structures were confirmed by ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopy, FTIR and ESI-MS, supporting monodentate carboxylate coordination and a solvent-dependent Sn(IV) coordination environment. Biological assays in HCT116 cells showed that the final bis-organosilane complexes were markedly more active than their aminobenzoate intermediates and, under several conditions, more effective than cisplatin. Sn(IV)-biSi-2 and Sn(IV)-biSi-3 reduced cell viability to approximately 30% at 0.5 μM after 5 days and to about 11% and 7%, respectively, at 12.5 μM. In repeated-treatment assays, these complexes maintained antiproliferative activity more efficiently than cisplatin, limiting resistance-like cell recovery. Western blot analysis revealed increased γ-H2AX, p53, cleaved caspase-3 and cleaved PARP, indicating DNA damage-associated apoptotic signaling. Overall, these results identify bis-organosilane triorganotin(IV) benzoates, especially Sn(IV)-biSi-2 and Sn(IV)-biSi-3, as promising metal-based anticancer candidates that sustain antiproliferative activity after repeated exposure in colorectal cancer cells and may contribute to strategies aimed at therapy-resistant colorectal tumors.