Chemotherapy is one of the main means to treat cancer. The discovery and application of platinum drugs have milestone significance for the development of cancer chemotherapy. According to statistics, about 50% of clinical cancer treatment programs contain platinum drugs. However, due to poor targeting, low bioavailability and in vivo deactivation, platinum drugs have some problems in clinical use, especially drug resistance, which seriously restricts their efficacy and long-term use. Many tumors are inherently resistant to platinum drugs, such as cisplatin, which is ineffective in the treatment of common gastrointestinal tumors. Even if the tumor has a good response to platinum drugs, with the accumulation of time and dose, it is easy to develop acquired drug resistance, which leads to treatment failure. Therefore, it is an important problem to overcome the drug resistance of platinum anticancer drugs. It is generally believed that nuclear DNA is the main target of platinum drugs. After the drug enters the cell, it covalently combines with DNA to form Pt DNA adduct. The damaged DNA can not be transcribed and copied normally, and then activate various signal pathways to lead to apoptosis. Therefore, if the DNA damage process of platinum (II) is inhibited, the tendency of apoptosis will be weakened, which will lead to drug resistance of tumor.
The primary challenge of platinum drugs is that there are a series of precise and efficient DNA damage repair systems in cells, such as the repair mechanism of DNA double strand break homologous recombination (HR) involving BRCA protein. The DNA repair function of tumor cells is particularly powerful, which can fully repair the DNA damage caused by chemotherapy drugs, which is one of the important reasons why platinum drugs are prone to drug resistance. According to the commonly accepted mechanism of platinum drugs, when platinum (II) damages DNA to a certain extent, it will trigger apoptosis signal transduction pathway and force cells into apoptosis process. However, DNA repair proteins in tumor cells, such as BRCA1 / 2, Rad51 and so on, which participate in homologous recombination and repair, will quickly recognize the damaged DNA and restore its structure to the original by some way, thus weakening the damage of DNA chain caused by platinum (II), and can not achieve the purpose of inducing apoptosis. On the other hand, the abnormal expression of anti apoptotic protein can also resist cell death induced by DNA damage. Therefore, the mechanism of DNA damage repair and the over activation of anti apoptotic protein are the two main reasons for the resistance of tumor cells to platinum drugs.
Tetravalent platinum complexes, as a new generation of platinum antitumor prodrugs, have been widely valued in recent years. They have octahedral spatial structure, large chemical reaction inertia, small side effects in the process of transportation in vivo, and axial ligands provide convenience for functional modification. It is generally believed that the platinum (IV) complex is stable in plasma and normal tissues. When it enters tumor cells, the oxygen deficient and high reducing environment makes it release active bivalent platinum species, which damages DNA and kills tumor cells. Recently, Guo Zijian, academician of Nanjing University and Wang Xiaoyong's research team introduced functional ligands that can inhibit DNA damage repair mechanism or anti apoptotic protein in the axial position of platinum (IV), and constructed a series of multifunctional tetravalent platinum prodrugs. By inhibiting DNA damage repair and inducing cell apoptosis, the aim of overcoming traditional platinum drug resistance was achieved.
（1） Tetravalent platinum complexes targeting homologous recombination repair (HR)
Platinum drugs enter tumor cells and form cross-linked products with DNA, which lead to DNA double helix distortion and replication block, and finally induce DNA double strand break and cell apoptosis. BRCA1 / 2 is two important tumor suppressor genes. They repair DNA with double strand breaks by participating in homologous recombination. Therefore, cancer patients with BRCA1 / 2 mutations are more sensitive to platinum chemotherapy. However, most patients have normal BRCA function, and only a few have BRCA 1 / 2 mutation, so platinum drugs often show serious drug resistance. To solve this problem, they designed two platinum (IV) - artesunate (Art) complexes (pt-art-i and pt-art-ii, figure 1) targeting HR key protein Rad51. Rad51 is the central protein of HR, which is mainly recruited and regulated by BRCA1 / 2. Its function is to form filaments at the ends of broken DNA chains, thus catalyzing the chain exchange reaction and initiating HR repair. For ovarian cancer and breast cancer cells that are not sensitive to platinum drugs and have normal BRCA function or homologous recombination function, the toxicity of double substituted pt-art-ii is significantly higher than that of cisplatin, reaching 13 times and 11 times respectively (Table 1). The mechanism studies showed that the two compounds can effectively enter the tumor cells and be reduced to active divalent platinum species and art. The former combines with DNA to induce DNA double strand breaks, while the latter down regulates Rad51, thus inhibiting Rad51 to form filaments (Fig. 1, 2), weakening the ability of DNA homologous recombination and repair. Because DNA double strand breaks can't be repaired in time, the tumor cells have significant apoptosis. The results showed that the introduction of art with down-regulated Rad51 function in the axial position of tetravalent platinum prodrug could overcome the resistance of BRCA normal tumor cells, which provided a useful reference for the design of new platinum drugs. The work was published in Chem. Commun. [1]
Figure 1. Structure and mechanism of pt-art-i and pt-art-ii
Table 1. IC50 values of pt-art-i and pt-art-ii on different cells (μ m, 72 h)
Figure 2. Inhibition of platinum (IV) - artesunate complex on homologous recombinant protein Rad51 in CAOV3 tumor cells
（2） Tetravalent platinum complexes targeting homologous recombination and apoptosis escape simultaneously
In addition to DNA damage repair, apoptosis escape is also an important reason for the resistance of tumor cells to platinum drugs. That is to say, tumor cells can also resist the killing effect of drugs by activating anti apoptosis pathway after DNA repair is inhibited. Therefore, to effectively overcome drug resistance, it seems that these two pathways should be intervened at the same time. Mcl-1 is an anti apoptotic protein of Bcl-2 family. It not only participates in the regulation of apoptosis, but also plays an important role in homologous recombination (HR). Therefore, targeting Mcl-1 may be able to interfere with DNA repair and apoptosis escape at the same time. According to this conclusion, the team designed two platinum (IV) - thiophene complexes 1 and 2 targeting Mcl-1 (Figure 3), which showed high toxicity to cisplatin resistant lung cancer and ovarian cancer cells, among which the inhibition effect of complex 2 on these two cells was 32 times and 61 times of cisplatin respectively (Table 2), the resistance index (RF) was also significantly reduced, and cisplatin resistant A549 / DDP cells were 2 and cisplatin resistant The RF of platinum was 0.9 and 5.0, respectively. The RF of A2780 / DDP cells to 2 and cisplatin was 0.7 and 7.23, respectively. These complexes also significantly inhibited tumor growth in mice (Fig. 4), with low systemic toxicity. Mechanism study shows that complex 2 can not only inhibit the expression of Mcl-1, but also the expression of HR protein Rad51 and BRCA2 (Fig. 5), thus inhibiting DNA double strand break repair and promoting apoptosis. These results suggest that intervention of HR repair and apoptosis escape pathway at the same time can overcome drug resistance more effectively. This unique mechanism of action has opened up a new way to design anti drug platinum complexes. The results were published in Chem. SCI. [2]
Figure 3. Structure and mechanism of complexes 1 and 2
Table 2. IC50 values of complexes 1 and 2 on different tumor cells (μ m, 72h)
Fig. 4. Changes of A549 tumor volume in 15 day period after intravenous injection of cisplatin (1.3 mg Pt kg-1), complex 1 or 2 (1.1 mg Pt kg-1) every 3 days in tumor bearing mice
Figure 5. Effects of complexes 1 and 2 on apoptosis related proteins and homologous recombinant proteins in A549 / DDP cells
The first author of the above research paper is Zhang Shuren, Ph.D. student, School of chemistry and chemical engineering, Nanjing University, and the corresponding authors are Professor Wang Xiaoyong and academician Guo Zijian.
1. Original text (scan or long press QR code, and then go to the original page after identification): rewards rational design of Rad51 targeting prodrugs: platinumiv – artesunate alignments with enhanced cytoxicity against BRCA professional ovarian and burst cancer cells Shuren Zhang, Hao Yuan, Yan Guo, Kun Wang, Xiaoyong Wang, Zijian guochem. Commun., 2018, 54, 11717-11720, DOI: 10.1039/c8cc06576d
2. Original text (scan or long press QR code, and then go to the original page after identification): intervening in apoptosis and DNA repair of cancer cells to ask cisplatin resistance by platform (IV) prodrugsshuren Zhang, Xuanmeng Zhong, Hao Yuan, Yan Guo, Dongfan song, Fen Qi, Zhenzhu, Xiaoyong Wang, Zijian guochem. SCI., 2020, 11, 3829-3835, DOI: 10.1039/d0sc00197j
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