Abstract
HER2-positive breast cancer is one of its most challenging subtypes, forming around 15-25% of the total cases. It is characterized by aggressive behavior and treatment resistance. On the other hand, poly (amidoamine) (PAMAM) dendrimers are widely used in drug delivery systems and gene transfection as carriers. PAMAMs can modulate gene expression and interfere with transactivation of the human epidermal growth factor receptor family members (HER1-4). Nevertheless, the outcome of PAMAMs on HER2-positive breast cancer remains unknown. Thus, in this study, we investigated the anti-cancer effects of different generations of PAMAM dendrimers (G4 and G6) and the outcome of their surface chemistries (cationic, neutral, and anionic) on HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data showed that PAMAM dendrimers, mainly cationic types, significantly reduce cell viability in a dose-dependent manner. More significantly, PAMAMs induce substantial cell apoptosis, accompanied by the up-regulation of apoptotic markers (Bax, Caspases-3, 8 and 9) in addition to down-regulation of Bcl-2. Moreover, our data pointed out that cationic PAMAMs inhibit colony formation compared to controls and other types of PAMAMs. The molecular pathway analysis of PAMAM exposed cells revealed that PAMAMs enhance JNK1/2/3 expression while blocking ERK1/2, in addition to EGFR1 (HER1) and HER2 activities, which could be the major molecular pathway behind these events. These observed effects were comparable to lapatinib treatment, a clinically used inhibitor of HER1 and 2 receptors phosphorylation. Our findings implicate that PAMAMs may possess important therapeutic effects against HER2-positive breast cancer via JNK1/2/3, ERK1/2, and HER1/2 signalling pathways.
Highlights
Breast cancer is the most common type of cancer among women worldwide, with increased incidence and mortality ratesAbbreviations: 7-AAD, 7-amino-actinomycin D; Bax, Bcl-2 Associated X; Bcl-2, B cell lymphoma-2; EGFR, Epidermal growth factor receptor; ErbB2, erythroblastic oncogene B; ERK, Extracellular-signal-regulated kinase; fetal bovine serum (FBS), Fetal bovine serum; FITC, Fluorescein isothiocyanate; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; JNK, c-Jun N-terminal kinase; poly (amidoamine) dendrimers (PAMAMs), poly(amidoamine) dendrimers; PE, Phycoerythrin; PVDF, Polyvinylidene difluoride.⇑ Corresponding authors: College of Pharmacy, QU Health, Qatar University, PO qa
The effect of PAMAM dendrimers (G4NH2, G6NH2, G6OH, G5.5COOH) on cell viability was assessed on human epidermal growth factor receptor type 2 (HER2)-positive breast cancer cells, SKBR3 and ZR75
This study reports the effect of PAMAMs on HER2-positive breast cancer and its underlying mechanism
Summary
Breast cancer is the most common type of cancer among women worldwide, with increased incidence and mortality rates⇑ Corresponding authors: College of Pharmacy, QU Health, Qatar University, PO qa Around 15–25% of total breast cancer cases are HER2-positive, where the human epidermal growth factor receptor type 2 (HER2) is overexpressed [3,4]. Despite anti-HER2 and cytotoxic chemotherapy, HER2 subtype exhibits many challenges, including aggressive behavior, early relapse, poor prognosis, and higher recurrence rate [4]. Along with hormonal therapy, current treatments for HER2-positive breast cancer include trastuzumab (a monoclonal antibody) and lapatinib (a tyrosine kinase inhibitor); they exhibit many limitations, mainly cardiac complications and chemo-resistance [5,6,7,8,9].
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