Thiolatia (THL), a zinc chelator, is a disulfide-containing antibiotic and antiangiogenic compound. THL has been shown to inhibit adhesion to vitronectin and tumor-induced angiogenesis in vivo by decreasing paxillin in human umbilical vein endothelial cells (HUVECs) (Minamiguchi et al., 2001); and to block Hsp27 phosphorylation by inducing endothelial cell adhesion and wound/tumor-driven angiogenesis in vitro (Jia et al., 2010). Moreover, THL inhibits JAMM domain-containing proteases such as PSMD14 through catalytic Zn²⁺ ion complexes with the enzyme’s active center (Lauinger et al., 2017).

PSMD14 is highly expressed in a variety of cancers and acts as an oncogene to promote tumor development and progression (Zhu et al., 2018); it has been suggested that PSMD14 may be involved in esophageal squamous cell carcinoma (ESCC) tumorigenesis (Ma et al., 2016; Seo et al., 2019; Lv et al., 2020). As shown in Figure 1A that THL reverses the epidermal mesenchymal transition (EMT) process (Lamouille et al., 2014; Fischer et al., 2015; Zheng et al., 2015) (e.g., upregulation of E-Cadherin, inhibition of mesenchymal marker expression) by blocking PSMD14-mediated deubiquitination of SNAIL and decreasing the stability of SNAIL protein (Liu et al., 2017; Perez et al., 2017; Wu et al., 2017; Li et al., 2018). In addition, THL interferes with cytoskeletal reorganization and inhibits the formation of invagination cristae, which is essential for cell motility, weakening the motility and invasive ability of tumor cells. It also enhances the sensitivity of cancer cells to cisplatin, reducing side effects by reducing the dose of cisplatin, resulting in patient benefit (Jing et al., 2021).

Traditional proteasome inhibitors (e.g., bortezomib, carfilzomib) have more serious toxic side effects and limited efficacy in solid tumors compared with specific target inhibitors such as THL (Hideshima et al., 2005; Li J. et al., 2017; Song et al., 2017). In contrast, THL, as a PSMD14-specific inhibitor, is more selective and may be a safer anti-metastatic drug by precisely regulating the EMT and chemo-sensitivity-related pathways, combining both anti-metastatic and chemo-sensitizing effects (Deshaies, 2014; Jing et al., 2021).

Sulfarotene (WYC-209) is advantageous in that it possesses negligible toxicity and highly selective inhibition of the growth and tumor-inducing ability of tumor reconstructive cells (TRCs) (Jiang et al., 2020) in various types of cancers. It is believed that sulfarotene blocks the activation of pro-tumorigenic signals downstream of RAS by upregulating retinoic acid receptor α (RARα) in hepatocellular carcinoma (HCC) TRCs and inhibiting the expression of SOS2 (Liceras-Boillos et al., 2018), a key mediator of the RAS signaling pathway (Sheffels et al., 2018; Schwartz et al., 2019; Wołoszynowska-Fraser et al., 2020) (Figure 1B). This pathway not only drives the self-renewal and tumorigenicity of TRCs (Li et al., 2015), but is also closely associated with resistance to drugs such as sorafenib. In multiple preclinical models, sulfarotene demonstrated efficient and selective inhibition of HCC TRCs (Qi et al., 2021).

Traditional targeted drugs (e.g., sorafenib) are limited in their clinical application due to tumor cell stemness-induced resistance and their inherent toxicity (Wei et al., 2019; Wang et al., 2020; Xia et al., 2020). By precisely targeting the RARα-SOS2-RAS axis and directly interfering with the stemness maintenance and resistance mechanisms of TRCs, sulfarotene not only overcomes the limitations of existing drugs, but also demonstrates a potent inhibitory effect on metastatic foci. It provides a highly promising therapeutic strategy to improve the prognosis of HCC patients (Qi et al., 2021).

Many anticancer drugs belong to the class IV of the Biopharmaceutical Classification System (BCS), which comprises substances with both low solubility in aqueous fluids and low apparent permeability. The high recurrence and metastasis of colorectal cancer (CRC) (Todaro et al., 2010) are often attributed to the maintenance of stemness in cancer stem cells (CSCs) (Batlle and Clevers, 2017), whose self-renewal, drug-resistant, and invasive properties lead to therapeutic failures (Zhang Z. et al., 2016). BMI-1 (B-cell-specific Moloney Murine Leukemia Virus Integration Site 1), as a key regulator of the stemness of CSCs (Kreso et al., 2014), is overexpressed in CRC and correlates with tumor progression and poor prognosis (Siddique and Saleem, 2012). Inhibition of BMI-1 can reverse the stemness of CSCs and has been applied to the treatment of colon cancer, myeloma and acute myeloid leukemia (Mourgues et al., 2015). Based on this, the investigators developed PTC209, a specific inhibitor against BMI-1 (Bolomsky et al., 2016).

To solve the problems of poor solubility, complex gastrointestinal environment and non-specific distribution faced by oral drug delivery (Mitragotri et al., 2014), the researchers developed a targeted delivery system based on poly (ethylene glycol)-poly (hydroxyglycolic acid) lactate (PEG-PLGA) nanoparticles (Wang et al., 2011; Mazzaferro et al., 2013; Lin et al., 2018). The nanoparticles were synthesized by a double emulsion method and modified with hyaluronic acid (HA) as a CD44/CD168-targeting ligand (HA-NPs-PTC209) (Huang et al., 2014; Choi et al., 2019; Leng et al., 2019), which significantly enhanced the targeting ability of the BMI-1 inhibitor (Zhang M. et al., 2016). The results of the in vivo antitumor experiments showed that HA-NPs-PTC209 significantly inhibited the growth and metastasis of CT26 orthogonal xenografts, which led to the in situ colon tumor accumulation in in situ colon tumors, thus reversing CSC stemness. The high in vitro stability of this targeted nano-example and the high permeability of the drug through the intestinal barrier offer the possibility of mitigating systemic adverse effects and improving therapeutic efficiency (Xu et al., 2019) (Figure 1C).

The high mortality rate of non-small cell lung cancer (NSCLC) is closely related to chemoresistance and metastasis mediated by cancer stem cells (CSCs) (Martins-Neves et al., 2018). Conventional platinum-based drugs (e.g., cisplatin) have limited efficacy due to the DNA damage repair ability and drug resistance of CSCs (Nagasaka and Gadgeel, 2018; Wang et al., 2019). The CK2 inhibitor HY1 was found to have a strong inhibitory effect on CSCs in A549 cells (Schwind et al., 2017). Taking advantage of the inherent CK2 specificity and CSC inhibition of HY1, by conjugating HY1 with an active platinum (II) unit (Czarnomysy et al., 2018), the researchers developed a novel CK2-specific platinum (II) compound, HY1-Pt, which achieves the reversal of drug resistance and the inhibition of CSCs through the synergistic effect of targeting protein kinase CK2 with platinum-based drugs (Purwin et al., 2016). It was demonstrated that HY1-Pt specifically inhibited CK2 activity, blocked its mediated stemness-promoting signaling pathways such as Hedgehog/Gli1 and Wnt/β-catenin, and downregulated the expression of CSCs markers (e.g., Nanog, Oct-4) (Lu et al., 2013; Wang et al., 2017). Furthermore, HY1-Pt could enhance platinum drugs-induced DNA damage by interfering with the phosphorylation of DNA repair proteins by CK2 to inhibit the tumor cell repair ability. In vitro experiments demonstrated that HY1-Pt showed potent cytotoxicity (IC₅₀ significantly lower than cisplatin) and selectively inhibited the formation of CSCs spheroids in A549/cDDP cells and in the A549/cDDP xenograft model, HY1-Pt significantly inhibited the tumor growth without triggering significant toxicity reactions.

Existing CK2 inhibitors (e.g., CX-4945) have limited clinical efficacy, while conventional platinum drugs are limited by drug resistance and toxicity. HY1-Pt’s synergistic effect through a “dual-targeting” strategy (CK2 inhibition + platinum DNA damage) is expected to improve the prospects for platinum-based therapies and to reverse the resistance to cisplatin (Wang et al., 2021b).

The high invasiveness and cisplatin resistance of esophageal squamous cell carcinoma (ESCC) are closely related to the maintenance of stemness in cancer stem cells (CSCs) (Najafi et al., 2019; Mao et al., 2021). The expression level of RAS-associated protein 1b (Rap1b), as a member of the RAS superfamily, has been confirmed to correlate positively with stemness of CSCs, and overexpression of Rap1b in ESCC positively regulates CSC proliferation, invasion, and stemness, making it a novel target for reversing ESCC drug resistance (Noguchi et al., 2015; Jia et al., 2017; Zhang et al., 2019). Guo et al. found that Rap1b was overexpressed in glioma stem cells (GSCs), and silencing Rap1b could effectively inhibit the growth and invasion of glioma cells (Guo et al., 2023). In addition, Rap1b has been shown to promote hematopoietic stem cell development by enhancing integrin-mediated cell adhesion (Rho et al., 2019).

Based on this, researchers have developed novel platinum (IV) complexes (e.g., complex-1) (Zhang et al., 2017) with the natural polyphenolic compound Salvigenin as a ligand to inhibit Rap1b and overcome cisplatin resistance through a dual mechanism. Complex-1, which consists of a platinum (IV) core conjugated with Salvigenin ligand, significantly downregulates cancer cell stemness by inhibiting Rap1b expression and blocking its mediated integrin signaling and Wnt/β-catenin/TCF pathway; and enhances the platinum accumulation in cisplatin-resistant cells (TE6/cDDP) and inhibits the DNA damage repair ability (Fang et al., 2019).

As the first platinum (IV) complex that potently inhibits Rap1b and effectively reverses cisplatin-induced drug resistance, complex-1 fills the gap that there is no effective solid molecule inhibitor for Rap1b, and provides a new way of thinking for the development of Rap1b inhibitors and overcoming cisplatin-induced drug resistance in cancer cells (Zhao et al., 2024).

Cantharidin (CTD), a terpenoid isolated from blister beetles and used in traditional Chinese medicine for the treatment of a variety of diseases and cancers (Deng et al., 2013), has been shown to be an inhibitor of protein phosphatase 2A (PP2A) and heat shock transcription factor 1 (HSF-1), both of which are potential anticancer targets (Kim et al., 2013; Li W. et al., 2017). As shown in Figure 1D, CTD significantly inhibits the proliferation of a variety of solid tumors and leukemia cells, including liver cancer, pancreatic cancer, and colon cancer, by inhibiting PP1/PP2A activity, inducing apoptosis, interfering with cell cycle arrest and autophagy (Wu et al., 2014; Shen et al., 2015). By inhibiting PP1/PP2A activity, inducing apoptosis, interfering with protein synthesis, and triggering cell cycle arrest and autophagy, CTD significantly inhibits the proliferation of hepatocellular carcinoma, pancreatic carcinoma, colon carcinoma, and other solid tumors as well as leukemia cells (Huang et al., 2011; Hsia et al., 2015b; Ji et al., 2015; Su et al., 2015; Su et al., 2016; Liu et al., 2018). In addition, CTD can reduce the expression of DNA damage repair-related proteins, enhance the sensitivity of cancer cells to radiotherapy, and alleviate the sequelae of chemotherapy in combination therapy (Kuo et al., 2015; Xu et al., 2018).

Studies have demonstrated that CTD inhibits cancer cell invasion and migration by targeting and regulating metastasis-related signaling pathways in a variety of cancer cells. For example, in gastric cancer, CTD inhibited migration by down-regulating the CCAT1-mediated PI3K/AKT pathway (Song et al., 2020); in bladder cancer cells, it blocked cell adhesion and invasion by inhibiting the p38/JNK1/2 MAPK pathway and decreasing the enzyme activity and expression of MMP-2/9. In addition, CTD inhibited metastatic potential by inhibiting the PI3K/AKT/mTOR and NF-κB pathways and reducing UPA protein and matrix metalloproteinase activities in lung cancer models (Hsia et al., 2016).

CTD can effectively inhibit metastasis in different kinds of cancer cells; and the action of CTD involves key pathways such as MAPK, Bcl2/Bax, Wnt/β-catenin, ERK, etc., which inhibit tumor growth and metastasis through cross-regulation (Wang et al., 2015; Gu et al., 2017; Chun et al., 2018). Among them, PI3K/AKT/mTOR and MAPK pathways have been widely proved to be the core targets of CTD against tumor metastasis, and CTD, as a multi-targeted anticancer agent, has demonstrated its unique advantages in inhibiting tumor growth, metastasis, and synergistic radiotherapy. However, the toxicity of CTD itself remains to be solved (Hsia et al., 2015a; Naz et al., 2020).