Department of Biochemistry, Faculty of Medicine, Eastern Mediterranean University, Via Mersin, Turkey.
Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul, Turkey.
Anticancer Agents Med Chem. 2022 Aug 4;22(16):2909-2918. doi: 10.2174/1871520622666220329175501.
Proteasome inhibitors target different pathways in cells and therefore are promising drugs in cancer therapy. The use of these inhibitors is approved mainly in hematological cancers, and recently many clinical trials and preclinical studies have been conducted on efficacy in solid tumors. Carfilzomib is a second-generation inhibitor and was developed to decrease the side effects of bortezomib. Although there are many valid therapies for breast cancer, resistance and recurrence are inevitable in many cases and the proteasomal system plays an important role in related pathways.
This study is a preliminary work to evaluate the combined effects of bortezomib and carfilzomib in four different breast cancer cells.
MDA-MB-231, MCF-7, UACC-2087, and SKBR-3 cell lines were used. Cell viability was determined using bortezomib and carfilzomib alone and in combination. Combination effect values were determined using the Chou- Talalay method. Apoptosis, proteasome activity, cleaved PARP, and HSP70 expressions were analyzed in the determined doses.
The response to the combination of the two inhibitors was different in four cell lines. Apoptosis was significantly higher in combination groups compared to carfilzomib in three cell lines except for SKBR-3, and higher in the combination group compared to bortezomib only in UACC-2087. Combination decreased cleaved PARP levels in MDA-MB-231 and MCF-7 and increased SKBR-3 compared to bortezomib. HSP70 levels decreased in combination with UACC-2087 and SKBR-3 compared to carfilzomib.
Taken together, the combination of the two inhibitors was more apoptotic compared to carfilzomib and apoptosis was higher only in UACC-2087 compared to bortezomib. This apoptosis data can not be directly correlated to the degree of proteasome inhibition, PARP cleavage, and HSP70 response.
蛋白酶体抑制剂靶向细胞中的不同途径，因此在癌症治疗中具有广阔的应用前景。这些抑制剂的使用主要在血液系统癌症中得到批准，最近在实体瘤中进行了许多临床试验和临床前研究。卡非佐米是一种第二代抑制剂，旨在减少硼替佐米的副作用。尽管乳腺癌有许多有效的治疗方法，但在许多情况下，耐药性和复发是不可避免的，而蛋白酶体系统在相关途径中起着重要作用。
本研究旨在初步评估硼替佐米和卡非佐米联合应用于四种不同乳腺癌细胞的效果。
使用 MDA-MB-231、MCF-7、UACC-2087 和 SKBR-3 细胞系。单独使用硼替佐米和卡非佐米以及联合使用这两种药物来测定细胞活力。使用 Chou-Talalay 方法确定联合作用值。在确定的剂量下分析凋亡、蛋白酶体活性、裂解的 PARP 和 HSP70 的表达。
在四种细胞系中，两种抑制剂联合使用的反应不同。除 SKBR-3 外，三种细胞系中联合组的凋亡率明显高于卡非佐米组，且 UACC-2087 细胞系中联合组的凋亡率高于硼替佐米组。与硼替佐米相比，联合组降低了 MDA-MB-231 和 MCF-7 中的裂解 PARP 水平，并增加了 SKBR-3 中的水平。与卡非佐米相比，联合组降低了 UACC-2087 和 SKBR-3 中的 HSP70 水平。
综上所述，与卡非佐米相比，两种抑制剂的联合使用更具促凋亡作用，且仅在 UACC-2087 中比硼替佐米更具促凋亡作用。这些凋亡数据不能直接与蛋白酶体抑制程度、PARP 裂解和 HSP70 反应相关联。
