## 2 Antiproliferative Activity of Schiff Bases Complexed with Transition Metals
The treatment with the Schiff base complex led to an up-regulation of p53 and Bax gene expression and a down-regulation of Bcl2 gene expression in the SCC cell line, concomitantly with the increase of caspase-3 and Bax proteins expression and down-regulation of Bcl-2 protein. A higher apoptotic effect induced by a Schiff base complex was shown by annexin V-FITC apoptosis kit compared to the cisplatin-treated group. These effects were markedly enhanced on the combination of Schiff base and cisplatin. [PERSON] et al. (2021) [48] reported the synthesis and biological evaluation of new Schiff bases incorporating sulfisoxazole and sulfamethoxazole and their Cu(II) complexes. The anticancer activity was evaluated against three human cancer cell lines with the sulfonamide B test. Complexes of ligand S1M-S1 with Cu(II) named Cu(S2M-S1)\({}_{2}\) (**11**) and Cu(S1M-S1)\({}_{2}\) (**12**) (Table 1) exhibited promising cytotoxic activity against breast (MCF7) cells (IC\({}_{50}\) = 40 \(\upmu\)M versus 5-fluorouracil, 5-FU, IC\({}_{50}\) = 0.10 \(\upmu\)M). Moreover, docking studies were carried out on these compounds, suggesting that hydrogen bonds seem to play a pivotal role in the reversible interaction of small molecules and proteins. In this case, the oxygen and nitrogen atoms on the sulfisoxazole ring, the oxygen atom of sulfonyl groups and oxygen and nitrogen atoms attached to the benzene ring are thought to be involved in the hydrogen bonds' formation. [PERSON] et al. (2021) [49] studied several complexes in which the \(N^{1}\),\(N^{2}\)-bis(furan-2-ylmethylene)-4-methylbenzene-1,2-diamine (L) is complexed with several metals, namely Ag(II), Cr(III), Fe(III), Co(II), Cu(II) and Cd(II) (**13-18**), and studied their cytotoxicity against the HepG2 cell lines. The IC\({}_{50}\) values were 12.9 \(\upmu\)g/mL, 14.8 \(\upmu\)g/mL, 7.31 \(\upmu\)g/mL, 8.53 \(\upmu\)g/mL, 17.1 \(\upmu\)g/mL and 1.95 \(\upmu\)g/mL, respectively. The cadmium(II) complex showed the highest cytotoxic activity, being more potent than vinblastine used as standard drug (IC\({}_{50}\) = 2.93 \(\upmu\)g/mL). Its activity was also higher with respect to that of the free ligand, suggesting an important role of the metal in the biological activity. [PERSON] et al. (2021) [50] studied the in vitro anticancer activity of the Schiff base ligands (\(N\)-(8-quinoyl)-X-salicylaldimine) and their complexes with Fe(II) and Fe(III) against the A549 human lung adenocarcinoma cell line. The Fe(III) complex (compound **19**, Table 1) showed an anticancer activity against the A549 cells (IC\({}_{50}\) = 10 \(\upmu\)M) higher than two well-known anticancer agents, i.e., etoposide and cisplatin (IC\({}_{50}\) = 19 and 16 \(\upmu\)M, respectively). [PERSON] et al. (2021) [51] analyzed two Schiff base ligands (L1, L2) and their complexes with Fe(III) and Zn(II) (**20,21**), studying their antitumor activity by means of potato disc tumor induction assay utilizing the _Agrobacterium tumefaciens_ strains. In this assay, the complexes of the two Schiff bases with Zn showed a better activity than the corresponding Fe compounds: ((L1)\({}_{2}\)Zn(Ac)\({}_{2}\) IC\({}_{50}\) = 6.81 \(\upmu\)g/mL and (L2)\({}_{2}\)Zn(Ac)\({}_{2}\) IC\({}_{50}\) = 7.58 \(\upmu\)g/mL versus (L1)\({}_{2}\)FeCl\({}_{3}\) IC\({}_{50}\) = 13.91 \(\upmu\)g/mL and (L2)\({}_{2}\)FeCl\({}_{3}\) IC\({}_{50}\) = 70.89 \(\upmu\)g/mL). Vincristine was used as positive control with an IC\({}_{50}\) value of 250 \(\upmu\)g/mL. Additionally, the safety of these compounds was also evaluated, using the brine shrimp microwell cytotoxicity assay. The obtained results confirmed that Zn complexes showed a higher cytotoxicity than the corresponding Fe ones (IC\({}_{50}\) > 134 \(\upmu\)g/mL); moreover, in both the assays were more pharmacologically active, as well. [PERSON] et al. (2021) [52] studied a Schiff base ligand and its two M(II) complexes formed with Co(II) and Ru(II).