Fatty acid synthase as a potential new therapeutic target for cervical cancer.

Fatty acid synthase (FASN) is the rate-limiting enzyme for the de novo synthesis of fatty acids in the cytoplasm of tumour cells. Many tumour cells express high levels of FASN, and its expression is associated with a poorer prognosis. Cervical cancer is a major public health problem, representing the fourth most common cancer affecting women worldwide. To date, only a few in silico studies have correlated FASN expression with cervical cancer. This study aimed to investigate in vitro FASN expression in premalignant lesions and cervical cancer samples and the effects of a FASN inhibitor on cervical cancer cells. FASN expression was observed in all cervical cancer samples with increased expression at more advanced cervical cancer stages. The FASN inhibitor (orlistat) reduced the in vitro cell viability of cervical cancer cells (C-33A, ME-180, HeLa and SiHa) in a time-dependent manner and triggered apoptosis. FASN inhibitor also led to cell cycle arrest and autophagy. FASN may be a potential therapeutic target for cervical cancer, and medicinal chemists, pharmaceutical researchers and formulators should consider this finding in the development of new treatment approaches for this cancer type.

Betulinic Acid-Brosimine B Hybrid Compound Has a Synergistic Effect with Imatinib in Chronic Myeloid Leukemia Cell Line, Modulating Apoptosis and Autophagy.

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the formation of the BCR-ABL (breakpoint cluster region-Abelson) oncoprotein. As many patients display therapeutic resistance, the development of new drugs based on semisynthetic products represents a new potential therapeutic approach for treating the disease. In this study, we investigated the cytotoxic activity, possible mechanism of action of a hybrid compound of betulinic acid (BA) and brosimine B in CML cell lines that are sensitive (K-562) and resistant (K-562R) to imatinib, in addition to evaluating lower doses of imatinib in combination with the hybrid compound. The effects of the compound, and its combination with imatinib, on apoptosis, cell cycle, autophagy and oxidative stress were determined. The compound was cytotoxic in K-562 (23.57 ± 2.87 µM) and K-562R (25.80 ± 3.21 µM) cells, and a synergistic effect was observed when it was associated with imatinib. Apoptosis was mediated by the caspase 3 and 9 intrinsic pathway, and cell cycle evaluation showed arrest at G0/G1. In addition, the hybrid compound increased the production of reactive oxygen species and induced autophagy by increasing LC3II and Beclin-1 mRNA levels. Results suggest that this hybrid compound causes the death of both imatinib-sensitive and -resistant cell lines and may hold potential as a new anticancer treatment against CML.