Molecular Mechanisms of Antitumor Activity of PAMAM Dendrimer Conjugates with Anticancer Drugs and a Monoclonal Antibody

Abstract

Taxanes are considered fundamental drugs in the treatment of breast cancer, but despite the similarities, docetaxel (doc) and paclitaxel (ptx) work differently. For this reason, it is interesting to identify mechanisms of antitumor activity of PAMAM dendrimer conjugates that carry docetaxel or paclitaxel and monoclonal antibody trastuzumab, specifically targeted to cells which overexpressed HER-2. For this purpose, the impact on the level of reactive oxygen species, the mitochondrial membrane potential, cell cycle distribution and the activity of caspases-3/7, -8 and -9 of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined and compared with free docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. Moreover, apoptosis and necrosis were studied using flow cytometry and confocal microscopy, respectively. Our studies show the complexity of the potential mechanism of cytotoxic action of PAMAM-drug-trastuzumab conjugates that should be sought as a resultant of oxidative stress, mitochondrial activation of the caspase cascade and the HER-2 receptor blockade.

Substantial cell apoptosis provoked by naked PAMAM dendrimers in HER2-positive human breast cancer via JNK and ERK1/ERK2 signalling pathways

“…For example, the intratracheal and intraperitoneal pathways were found to be safe in avoiding inflammatory responses caused by cationic PAMAMs compared to the intravenous route by slowing their release [20] , [50] . Moreover, a targeted delivery system of PAMAMs linked to trastuzumab was also proposed by different studies, which creates a selectivity towards HER2-positive breast cancer cells rather than other cells [21] , [51] , [52] .…”

Combination of Copper Metallodendrimers with Conventional Antitumor Drugs to Combat Cancer in In Vitro Models

“…The open channels result in a collapse of the mitochondrial potential and additional increased production of ROS. The consequence of these changes occurring in the mitochondria can be cell death [ 41 , 42 , 43 ]. Therefore, we analyzed the changes of mitochondrial potential (ΔΨ m ) in the presence of the studied nanocomplexes and compared these results with the data obtained for ROS level.…”

“…It is known that mitochondrial depolarization is characteristic of the early stages of apoptosis [ 41 , 42 , 44 ]. Thus, the percentage of apoptotic and necrotic cells in the cell suspension was determined after treatment with dendrimer/drug complexes.…”

A Review on Drug Delivery System for Tumor Therapy

“…Furthermore, the level of ROS, the mitochondrial membrane potential, cell cycle distribution, and the activity of caspases 3/7, 8, and 9 of PAMAM-DTX-TZ conjugates were determined and compared with free DTX. These findings could help to develop a better therapeutic profile with HER2-positive breast cancer for DTX (Figure 10) (Kulhari et al, 2016;Marcinkowska et al, 2019a;Marcinkowska et al, 2019b).…”