Abstract
PI3K/Akt signaling is one of the most frequently dysregulated pathways in cancer, including triple-negative breast cancer. With considerable roles in tumor growth and proliferation, this pathway is studied as one of the main targets in controlling the therapies’ efficiency. Nowadays, the development of nanoparticle–drug conjugates attracts a great deal of attention due to the advantages they provide in cancer treatment. Hence, the main purpose of this study was to design a nanoconjugate based on single-walled carbon nanotubes functionalized with carboxyl groups (SWCNT-COOH) and cisplatin (CDDP) and to explore the potential of inhibiting the PI3K/Akt signaling pathway. MDA-MB-231 cells were exposed to various doses (0.01–2 µg/mL SWCNT-COOH and 0.00632–1.26 µg/mL CDDP) of SWCNT-COOH-CDDP and free components for 24 and 48 h. In vitro biological tests revealed that SWCNT-COOH-CDDP had a high cytotoxic effect, as shown by a time-dependent decrease in cell viability and the presence of a significant number of dead cells in MDA-MB-231 cultures at higher doses. Moreover, the nanoconjugates induced the downregulation of PI3K/Akt signaling, as revealed by the decreased expression of PI3K and p-Akt in parallel with PTEN activation, the promotion of Akt protein degradation, and inhibition of tumor cell migration.
Highlights
Triple-negative breast cancer (TNBC) represents a special molecular subtype of breast cancer (BC) defined by the lack of three molecular biomarkers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) [1].TNBC accounts for approximately 15–20% of total BC cases worldwide [1,2], is the most aggressive and heterogeneous subtype of BC [3], and, compared with other molecular subtypes of BC, it is associated with a poor prognosis, aggressive clinical behavior, low survival rates after recurrence, and early metastasis [2,4]
We referred to CDDP, a platinum-based drug used in cancer therapy which has been used for conjugation with carboxyl-functionalized SWCNTs
Our data revealed the following main conclusions: (1) breast cancer cell viability decreased in a time- and dose-dependent manner after treatment with SWCNT-COOH-CDDP compared with free CDDP and SWCNT-COOH, which did not induced significant modifications; (2) the nanoconjugates induced cell death in MDA-MB-231 cultures after 24 and 48 h of treatment, with a dose of 0.5 μg/mL
Summary
TNBC accounts for approximately 15–20% of total BC cases worldwide [1,2], is the most aggressive and heterogeneous subtype of BC [3], and, compared with other molecular subtypes of BC, it is associated with a poor prognosis, aggressive clinical behavior, low survival rates after recurrence, and early metastasis [2,4]. TNBC tumors present high invasivity, increased expression of proliferation markers, high growth rate, and can rapidly metastasize to the brain, lungs, and liver [1,2]. One signaling pathway frequently dysregulated in TNBC and associated with uncontrolled cell proliferation, metabolism, and survival, which leads to the development and progression of cancer, is PI3K/Akt/mTOR [5].
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