Abstract
Apoptosis signaling pathways, drug resistance, and metastasis are important targets to develop new cancer treatments. We developed cholesterol-coated Poly(d,l-Lactide-co-Glycolic Acid) (PLGA) nanoparticles for effective encapsulation and delivery of retinoic acid and oxaliplatin to analyze their antitumor activity in colorectal cancer. The cell viability and proliferation of tumoral cells lines (CT-26 and SW-480) decreased when compared to control in vitro after treatment with the nanoparticles. In addition, apoptosis of CT-26 cells increased. Importantly, cytoprotection of nontumor cells was detected. Expression of pro-apoptotic proteins was upregulated, while anti-apoptotic proteins were downregulated either in vitro or in vivo. In addition, drug resistance and metastasis factors were downregulated in vivo. Human colorectal tumors that highly expressed BCL-2 and Ki-67 had a greater tendency towards death within 60 months. Our results show that loading oxaliplatin combined with retinoic acid and cholesterol in a nanoparticle formulation enables determination of optimal antitumor activity and subsequent treatment efficacy.
Highlights
Colorectal cancer (CRC) is the third most commonly occurring malignancy around the world with significant morbidity and mortality rates
Our analysis showed significant fas-associated protein with death domain (FADD) staining for NPs 1 (5 μg/mL, p < 0.05) and NPs 2 (5 μg/mL, p < 0.05) only 48 h after treatment
We demonstrated that increased expression of BCL-2 and caspase-8 is associated with proliferation (Ki-67), a high invasion grade, and a positive lymph node status
Summary
Colorectal cancer (CRC) is the third most commonly occurring malignancy around the world with significant morbidity and mortality rates. Evasion of apoptosis is one of the hallmarks of cancer, in general, and correlated to drug resistance and metastatic spread, which urges the development of new drugs [5,6,7]. Apoptosis occurs through the extrinsic pathway or intrinsic pathway. Both pathways converge at the activation of caspase-3, which induces other caspases downstream of caspase-3 and eventually leads to apoptosis of the cancer cells [6,8]. Tumor resistance to OXA treatment is not uncommon and can occur via a mutation in the intrinsic apoptosis pathway, which results in metastatic spread [7,11]. Neurotoxicity through reversible sensory neuropathy or chronic cumulative neuropathy is frequently observed [12]
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