## 1 Introduction  
According to the World Health Organization (WHO), cancer is the second most common cause of death worldwide [1]. In 2022, there were over 19 million new cancer cases and nearly 10 million deaths caused by this disease [2]. Colorectal cancer (CRC) is the second most commonly diagnosed cancer in women and the third most commonly diagnosed cancer in men worldwide [3]. It is estimated to be responsible for 9.4% of cancer-related deaths. Moreover, it has been estimated that, by 2040, the global burden of cancer will have accounted for as many as 28.4 million cases [4,5]. This indicates an emerging problem posed to current medicine and suggests inefficiency of the present anticancer therapies, especially in the case of cancer characterized by the multidrug resistance (MDR) phenotype [6]. Over the last decade, the 4-thiazolidinone-based compounds (4-TZD) have gained increasing attention in the context of the searching for new pharmaceuticals [7]. 4-TZD are promising compounds in the new drug design, as they can serve as a tool for manipulating physicochemical properties such as lipophilicity, polarity, and they even possess a hydrogen bonding ability [8]. These properties make them attractive pharmacokinetically and toxicologically [7]. Among the best-known subtypes are 5-ene-2-amino-4-thiazolidinones and thiopyrano[2,3-\(d\)] thiazoles [9]. The anticancer properties of 4-TZD derivatives have been repeatedly described and proved in the various literature reports [10, 11, 12]. Researchers demonstrated inter alia the ability of 7,8-dimethoxy-1-oxo-1\(H\)-isothiochemene-3-carboxylic acid (4-phenylthiazol-2-yl)-amide (Les-3266) to decrease the metabolic activity in human tongue squamous cell carcinoma cells (SCC-15) (Figure 1) [10]. Metabolic activity-reducing properties were also shown by 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester (Les-6009) in normal human fibroblasts (B)), lung carcinoma (A549), and neuroblastoma (SH-SYSY) cells (Figure 1) [11]. Interestingly, many papers suggest engagement of the peroxisome proliferator-activated receptor gamma (PPARv) in the biological activity of many 4-TZD derivatives [13]. Peroxisome proliferatorator-activated receptors (PPARs) act as transcription factors regulating the expression of many genes engaged inter alia in oxidative stress response, inflammation, and drug metabolism [14]. Among PPARs, PPARy is considered to be a promising target in the modern anticancer therapy due to its regulatory role in cell death, proliferation,  
Figure 1: Structures of 4-thiazolidinone-based derivatives mentioned in the present study. and angiogenesis [15]. [PERSON] et al. have proved the anticancer activity of certain 4-TZD derivatives, namely 5Z-(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one (Les-236) in human cancer cells such as a A549, SCC-15, SH-SY5Y, and colorectal adenocarcinoma (CACO-2) cells [12]. It was proven that these compounds are able to increase lactate dehydrogenase (LDH) release and act as inductors of apoptosis (measured by caspase-3 activity) in a concentration range between 1 \(\upmu\)M and 100 \(\upmu\)M [12]. Moreover, 4-TZD-based thiopyrano[2,3-_d_] thiazole derivatives namely _rel_-N-(2,4-dichlorophenyl)-2-[(5_a_R_,11b_R_)-2-oxo-5a,11b-dihydro-2\(H\),5_H_-chromen[4\(J\),4\(J\),5_]thiopyrano[2,3-_d_][1,3]thiazol-3(6_H_)-yl]acetamide (Les-2194) exerted cytotoxic effects on SCC-15 cells [16]. A similar cytotoxic effect on SCC-15 cells was also exerted by 3-[2-[5-(4-dimethylaminophenyl)-3-phenyl-4,5-dihydroxyrazolo-1-yl]-4-oxo-4,5-dihydro-1,3-thiazol-5-ylidene)-2,3-dihydro-1_H_-indol-2-one (Les-3640) [9]. Importantly, 4-TZD-based derivatives can act as PPARy agonists or antagonists, which has recently been shown inter alia by [PERSON] et al. and [PERSON] et al. [10,17]. However, there are no reports on the impact of Les-4368 and Les-4370 on PPARy-induced toxicity in CACO-2.