Musa Sanaa, Amara Noor, Selawi Adan, Wang Junbiao, Marchini Cristina, Agbarya Abed, Mahajna Jamal
Department of Nutrition and Natural Products, Migal-Galilee Research Institute, Kiryat Shmona 11016, Israel.
Department of Biotechnology, Tel-Hai College, Kiryat Shmona 11016, Israel.
Cancers (Basel). 2024 Jul 7;16(13):2479. doi: 10.3390/cancers16132479.
Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC).
化疗耐药是癌症治疗中的主要障碍，常常导致疾病进展和不良预后。它通过多种机制产生，如基因突变、药物外排泵、DNA修复增强以及肿瘤微环境的改变。这些过程使得癌细胞在化疗情况下仍能存活，凸显了需要新策略来克服耐药性并提高治疗效果。克唑替尼是第一代多靶点激酶抑制剂，已获美国食品药品监督管理局（FDA）批准用于治疗ALK阳性或ROS1阳性的非小细胞肺癌（NSCLC）、难治性炎性（ALK）阳性肌纤维母细胞瘤（IMT）以及复发/难治性ALK阳性间变性大细胞淋巴瘤（ALCL）。克唑替尼存在两种对映体形式：（R）-克唑替尼及其镜像（S）-克唑替尼。据推测，R-异构体负责此处所述的各种过程。另一方面，S-异构体对MTH1（一种对DNA修复机制很重要的酶）表现出强烈抑制作用。研究表明，克唑替尼是一种有效的多激酶抑制剂，可靶向多种激酶，如c-Met、天然型/T315I Bcr/Abl和JAK2。其作用机制涉及ATP结合的竞争性抑制和变构抑制，特别是对Bcr/Abl的抑制。克唑替尼与聚ADP核糖聚合酶抑制剂（PARP）联合使用时显示出协同效应，尤其是在携带BRCA基因突变的卵巢癌中。此外，克唑替尼针对许多p53突变癌症中的一个关键脆弱点。与野生型p53不同，p53突变体促进癌细胞存活。克唑替尼可导致p53突变体降解，使这些癌细胞对DNA损伤物质敏感并触发细胞凋亡。有趣的是，其他报告表明克唑替尼具有抗菌活性，可靶向革兰氏阳性菌，并且对耐药菌株也有活性。总之，克唑替尼通过多种机制发挥抗肿瘤作用，包括抑制激酶和恢复药物敏感性。强调了克唑替尼在联合治疗中的潜力，特别是在p53突变发生率高的癌症中，如三阴性乳腺癌（TNBC）和高级别浆液性卵巢癌（HGSOC）。
