Apoptosis is a physiological, programmed process of cell death. It plays an important role in embryonic development, tissue and organ formation, as well as in the clearance of senescent and diseased cells. The loss of the ability of cells to undergo apoptosis due to various environmental and genetic factors is one of the key factors in the occurrence and development of tumors, and stimulating and restoring the ability of tumor cells to undergo apoptosis is an effective way to prevent and treat tumors. Multidrug resistance (MDR) is a phenomenon in which tumor cells develop cross-resistance to other chemotherapeutic drugs with different molecular structures and mechanisms of action after a drug has become resistant to tumor cells. The mechanisms of MDR are complex, and studies have shown that apoptotic escape (increased resistance to apoptosis) is one of the important mechanisms. In this paper, we review the link between the important factors associated with apoptotic escape and the mechanism of MDR formation to provide a reference for the study of overcoming MDR. 1 P-glycoprotein-mediated apoptotic escape and MDR The most advanced study on the mechanism of MDR generation is the study of the function of P-glycoprotein (P-gp), a drug transport pump expressed by drug-resistant cells. Further studies revealed that P-gp has an apoptosis-inhibiting effect, and this finding established an organic link between tumor drug resistance and apoptosis tolerance. P-gp was shown to inhibit the induction of apoptosis by a variety of factors, including cytotoxic drugs, free radicals, and radiation-induced cystathione-aspase (caspase-dependent apoptosis. For example, upregulation of P-gp expression prevented cadmium and reactive oxygen species-induced apoptosis in renal proximal tubule cells, and studies on mdr1-transfected cells further demonstrated that P-gp inhibited radiation-induced caspase-dependent apoptosis. gp inhibited the function of caspase-3-dependent apoptosis in cells: using low-temperature stimulation, a large number of L1210/DNM cells underwent G1 phase block and apoptosis, and caspase-3 activity was significantly higher than that of L1210 cells. However, when the caspase-3 inhibitor Z-VAD-fmk was added, the induction of drug-resistant cell cycle arrest and apoptosis by cryostimulation was significantly reversed. Similarly, with a similar cell line, Gibalova et al. demonstrated that P-gp reduced the sensitivity of L1210 to cisplatin by inhibiting caspase-3 activation. In addition, P-gp did not directly inhibit the formation of the Fas ligand-induced death-inducing signaling complex, but it inhibited the subsequent activation of caspase-8 that would occur, thereby inhibiting apoptosis induced by the Fas death receptor pathway. Recently, this theory was further confirmed when Kater et al. showed that titanocene Y is a compound that mediates apoptosis via Fas (mutation of the Fas-associated death domain by transfection does not cause apoptosis). Thus, P-gp may inhibit caspase-dependent apoptosis by inhibiting caspase-3 and caspase-8 activation. 2 p53 and MDR p53 gene is an oncogene related to tumor development, involved in the regulation of cell growth, differentiation and death, and plays an important role in the process of apoptosis. p53 gene mutation or its loss of function has a significant effect on apoptosis. The use of molecular biology techniques such as gene transfer to reconstruct the expression and biological activity of the p53 gene can also have a significant impact on apoptosis. 2.1 p53 and apoptosis Most current chemotherapeutic agents can cause DNA damage, activate DNA-dependent protein kinases and ataxia capillary dilatation mutant proteins, phosphorylate wild-type P53 proteins, increase stability, and block cells in the G1 phase to complete repair or initiate apoptosis. Mutations or deletions of p53 are commonly seen in tumor cells, resulting in the inability of tumor cells to block in the G1 phase, contributing to the proliferation of abnormal cells or the inability to initiate apoptosis and develop drug resistance. Heinlein et al. studied p53 mutations in transgenic mice and observed that mutant p53 caused mammary tumor proliferation without affecting genomic stability. Down-regulation of MSP/Mst1 gene expression by mutant p53 also induced anti-apoptotic ability in tumor cells, and application of RNA interference technology to knock down endogenous MSP well mimicked the MSP transcriptional repression induced by overexpression of mutant p53 and caused H1299 lung cancer cells to possess stronger drug resistance. The upregulation of EGR1 expression caused by mutant p53 could also lead to drug resistance by making tumor cells resistant to apoptosis. scian et al. observed that the introduction of mutant p53 in H1299 cells activated the nuclear factor-κB2 (NF-κB2) pathway and made them resistant to drugs, and silencing NF-κB2 could re-sensitize cells resistant to pedialyte glycosides, cisplatin, carboplatin, etc. to these drugs. suggesting that mutant p53 may reduce drug sensitivity of tumor cells through the NF-κB2 pathway. weisz et al. further investigated this phenomenon and revealed that mutant p53 regulates NF-κB2 activation through tumor necrosis factor. 2.2 p53 and P-gp 2.2.1 Mutant p53 is regulating the expression of P-gp: p53 mutations mostly occur in the central sequence specific DNA binding region. Most researchers of mdr-1 gene promoter regulation also use p53 mutated in this region. mutant phenotypes at sites 281 and 175 are more common and can significantly activate the mdr1 promoter in many cell lines. kanagasabai et al. used MCF-7/ADR cells as a model and found that inhibition of heat shock factor 1, depleted heat shock protein 27 both stimulate mutant Kim et al. showed that mutant p53 directly regulates mdr1 gene expression at the transcriptional level. Therefore, removal of mutant p53 inhibits mdr1 and P-gp expression. 2.2.2 Wild-type p53 negatively regulates P-gp expression: both p53 and mdr1 genes are associated with tumor chemoresistance, and the interconnection of these two molecules has received attention. scian et al. suggested that wild-type p53 interacts with transcription factors such as TATA box binding proteins, which in turn inhibits mdr1 expression. qi et al. by recombinant adenovirus containing p53 gene, the By recombinantly expressing wild-type p53 in the highly P-gp resistant cell line MCF-7/ADR, Qi et al. showed a significant decrease in P-gp in resistant cells, an 18.1-fold increase in sensitivity to the drug, and a decrease in the IC50 value for doxorubicin from 4.54 mg/L ± 0.91 mg/L to 0.26 mg/L + 0.11 mg/L. 3 Bcl-2 family and MDR The Bcl-2 family has been identified The regulation of apoptosis by the Bcl-2 family depends on the interaction between its members, which can be divided into two categories: anti-apoptotic proteins, including more than ten members such as Bcl-2, and pro-apoptotic proteins, including more than ten members such as Bax. The regulation of apoptosis by the Bcl-2 family depends on the interactions between its members, which form a regulatory network of apoptosis by forming homodimers or heterodimers. The effective levels of anti-apoptotic and pro-apoptotic proteins determine whether apoptosis occurs or not: when the pro-apoptotic protein Bax forms a homodimer, the mitochondrial permeability transport pore forms and opens, leading to apoptosis; if the effective level of anti-apoptotic protein Bcl-2 or Bcl-xL is high, it will form a heterodimer with Bax and inhibit the occurrence of apoptosis. Zhu et al. found that m1R-181b expression was down-regulated in human gastric cancer multidrug-resistant SCC7901/VCR cells, and up-regulation of miR-181b targeted to regulate the anti-apoptotic protein Bcl-2 and thus down-regulated its protein level, which could partially reverse the multidrug-resistant phenotype of SGC7901/VCR. Similarly, Wisdom et al. found that m1R-125b was significantly low expressed in human gastric cancer MDR cell line SGC7901/VCR, while anti-apoptotic proteins Bcl-2 and Mcl-1 were significantly high expressed. Up-regulation of miR-125b targeting inhibition of Bcl-2 and Mel-1 expression significantly increased the multidrug resistance phenotype of human gastric cancer MDR cell line SGC7901/VCR cells to multiple chemotherapeutic agents sensitivity. 4 Conclusion There is a close relationship between apoptotic escape and MDR of tumors. Apoptotic escape leads to the survival of tumor cells and the development of multidrug resistance. It is believed that with the continuous in-depth research on apoptosis and MDR in the future, more ideas and ways will be provided to overcome the multidrug resistance of tumors. 2012-12-24 08:53 Source: International Journal of Oncology Author: Fei Sun et al.