A novel tin based hydroxamic acid complex induces apoptosis through redox imbalance and targets Stat3/JNK1/MMP axis to overcome drug resistance in cancer

Undesired toxicity and emergence of multidrug resistance (MDR) are the major impediments to the successful application of organotin-based compounds against cancer. Since oxalyl-bis(N-phenyl)hydroxamic acid (OBPHA) exerts significant efficacy against cancer, we believe that derivatives of OBPHA including organotin molecule can show a promising effect against cancer. Herein, we have selected three previously characterized OBPHA derivatives viz., succinyl-bis(N-phenyl)hydroxamic acid (SBPHA), diphenyl-tin succinyl-bis(N-phenyl)hydroxamic acid (Sn-SBPHA), malonyl-bis(N-phenyl)hydroxamic acid (MBPHA) and evaluated their antiproliferative efficacy against both drug-resistant (CEM/ADR5000; EAC/Dox) and sensitive (CCRF-CEM; HeLa; EAC/S) cancers. Data revealed that Sn-SBPHA selectively targets drug-resistant and sensitive cancers without inducing any significant toxicity to normal cells (Chang Liver). Moreover, shortening of the backbone of SBPHA enhances the efficacy of the newly formed molecule MBPHA by targeting only drug-sensitive cancers. Sn-SBPHA induces caspase3-dependent apoptosis through redox-imbalance in both drug-resistant and sensitive cancer. Sn-SBPHA also reduced the activation and expression of both MMP2 and MMP9 without altering the expression status of TIMP1 and TIMP2 in drug-resistant cancer. In addition, Sn-SBPHA reduced the activation of both STAT3 and JNK1, the transcriptional modulator of MMPs, in a redox-dependent manner in CEM/ADR5000 cells. Thus, Sn-SBPHA targets MMPs by modulating STAT3 and JNK1 in a redox-dependent manner. However, MBPHA and SBPHA fail to target drug resistance and both drug-resistant and sensitive cancer respectively. Furthermore, Sn-SBPHA significantly increases the lifespan of doxorubicin-resistant and sensitive Ehrlich Ascites Carcinoma-bearing mice without inducing any significant systemic toxicity. Therefore, Sn-SBPHA has the therapeutic potential to target and overcome MDR in cancer.非预期毒性与多药耐药（multidrug resistance, MDR）的产生，是有机锡类化合物用于癌症治疗的主要阻碍。鉴于草酰双(N-苯基)羟肟酸 (oxalyl-bis(N-phenyl)hydroxamic acid, OBPHA) 对癌症具有显著的治疗功效，我们推测其衍生物（包括含有机锡分子的衍生物）有望展现出良好的抗癌活性。本研究选取了3种已被表征的OBPHA衍生物，即琥珀酰双(N-苯基)羟肟酸 (succinyl-bis(N-phenyl)hydroxamic acid, SBPHA)、二苯基锡琥珀酰双(N-苯基)羟肟酸 (diphenyl-tin succinyl-bis(N-phenyl)hydroxamic acid, Sn-SBPHA) 以及丙二酰双(N-苯基)羟肟酸 (malonyl-bis(N-phenyl)hydroxamic acid, MBPHA)，并评估了它们对耐药型（CEM/ADR5000、EAC/Dox）与敏感型（CCRF-CEM、HeLa、EAC/S）癌症细胞的抗增殖活性。实验数据显示，Sn-SBPHA可选择性靶向耐药型与敏感型癌细胞，且不会对正常细胞（张氏肝细胞, Chang Liver）产生显著毒性。此外，缩短SBPHA的分子骨架可得到新化合物MBPHA，后者仅靶向敏感型癌细胞，其抗癌活性得到提升。Sn-SBPHA可通过引发耐药型与敏感型癌细胞的氧化还原失衡，诱导半胱天冬酶3 (caspase3) 依赖性细胞凋亡。在耐药型癌细胞中，Sn-SBPHA还可降低基质金属蛋白酶2 (MMP2) 与基质金属蛋白酶9 (MMP9) 的激活与表达水平，且不会改变金属蛋白酶组织抑制剂1 (TIMP1) 与金属蛋白酶组织抑制剂2 (TIMP2) 的表达状态。此外，在CEM/ADR5000细胞中，Sn-SBPHA可通过氧化还原依赖性方式，抑制作为基质金属蛋白酶 (MMPs) 转录调控因子的信号转导与转录激活因子3 (STAT3) 与c-Jun氨基末端激酶1 (JNK1) 的激活。因此，Sn-SBPHA可通过氧化还原依赖性方式调控STAT3与JNK1，从而靶向基质金属蛋白酶家族。然而，MBPHA与SBPHA的抗癌谱存在局限：MBPHA仅能靶向敏感型癌细胞，无法作用于耐药型癌症；而SBPHA则既无法靶向耐药型癌症，也未能对敏感型癌症展现出理想的抑制效果。此外，Sn-SBPHA可显著延长阿霉素 (doxorubicin) 耐药型与敏感型艾氏腹水癌 (Ehrlich Ascites Carcinoma) 荷瘤小鼠的生存期，且不会引发明显的全身毒性。因此，Sn-SBPHA具备靶向并克服癌症多药耐药的治疗潜力。