The Role of Nitrosamine (NNK) in Breast Cancer Carcinogenesis.

Smoking cigarettes is one of the most concerning issues that leads to tobacco-related cancers and can even result in death. Therefore, these issues should be addressed with a great sense of urgency with low-cost and simple approaches. Over the past several years, the scientific community has attempted to find solutions to overcome this issue. Thus, a large number of excellent studies have been reported in this field, and summarizing these results and providing important roadmaps for future studies is currently of great importance. Finding an outstanding solution to address aforementioned issue would be of great value to the community and to the social. Tobacco contains thousands of chemicals, and sixty-nine compounds have been established as human carcinogens; specifically, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the strongest carcinogen among the tobacco-specific nitrosamines. Tobacco carcinogens are also linked to mammary gland pathogenesis and increased risk of developing many cancers, including breast cancer, the most common cancer in women worldwide. This mini-review summarizes the role of NNK and the mechanisms of its receptor, nicotine acetylcholine receptor (nAChR), signaling in breast cancer based on publications identified using the keywords "secondhand smoke (SHS)", "Nitrosamines" and "breast cancer". Furthermore, this review considers the risk of NNK to the public in an effort to reduce exposure to SHS in women and their chances of developing breast cancer.

Combination therapy with doxorubicin-loaded galactosylated poly(ethyleneglycol)-lithocholic acid to suppress the tumor growth in an orthotopic mouse model of liver cancer.

Despite advances in technology, neither conventional anti-cancer drugs nor current nanoparticle (NP) drugs have gained substantial success in cancer treatment. While conventional chemotherapy drugs have several limitations such as low potency, poor in vivo stability and limited bioavailability, non-specific targeting of NP drugs diminishes their potency at actual target sites. In addition, the development of drug resistance to anti-cancer drugs is another challenging problem. To overcome these limitations, we aimed to develop a polymer-drug conjugate, which functions as an active NP drug and drug carrier both, to deliver a chemotherapeutic drug for combination therapy. Accordingly, we made targeting NP carrier of lithocholic acid-poly(ethylene glycol)-lactobionic acid (LPL) loading doxorubicin (Dox) to produce Dox/LPL NPs. The cellular uptake of Dox/LPL NPs was relatively higher in human liver cancer cell line (SK-HEP-1) due to galactose ligand-asialoglycoprotein receptor interaction. Consequently, the cellular uptake of Dox/LPL NPs led to massive cell death of SK-HEP-1 cells by two different mechanisms, particularly apoptotic activity by LPL and mitotic catastrophe by Dox. Most importantly, Dox/LPL NPs, when administered to orthotopic xenograft model of liver cancer, greatly reduced proliferation, invasion, migration, and angiogenesis of liver tumor in vivo. Thus, this study exemplifies the superiority of combination therapy over individual NP drug or conventional small molecule drug for cancer therapy. Overall, we present a promising approach of combinatorial therapy to inhibit the hepatic tumor growth and metastasis in the orthotopic xenograft model mice, thus representing an effective weapon for cancer treatment.

Suppression of Tobacco Carcinogen-Induced Lung Tumorigenesis by Aerosol-Delivered Glycerol Propoxylate Triacrylate-Spermine Copolymer/Short Hairpin Rab25 RNA Complexes in Female A/J Mice.

BACKGROUND: Rab25, a member of Rab family of small guanosine triphosphatase, is associated with progression of various types of human cancers, including lung cancer, the leading cause of cancer-associated deaths around the globe. METHODS: In this study, we report the gene therapeutic effect of short hairpin Rab25 RNA (shRab25) on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice. Initially, mice (6 weeks old) were injected with single dose of NNK (2 mg/0.1 mL saline/mouse) by intraperitoneal injection to induce the tumor. Eight weeks later, shRab25 was complexed with glycerol propoxylate triacrylate-spermine (GPT-SPE) copolymer and delivered into tobacco-induced lung cancer models through a nose-only inhalation system twice a week for 2 months. RESULTS: GPT-SPE/shRab25 largely decreased the tobacco-induced tumor numbers and tumor volume in the lungs compared to GPT-SPE- or GPT-SPE/shScr-delivered groups. Remarkably, aerosol-delivered GPT-SPE/shRab25 significantly decreased the expression level of Rab25 and other prominent apoptosis-related proteins in female A/J mice. The apoptosis in these mice was determined by detecting the expression level of Bcl-2, proliferating cell nuclear antigen, Bax, and further confirmed by TUNEL assay. CONCLUSIONS: Our results strongly confirm the tumorigenic role of Rab25 in tobacco carcinogen-induced lung cancer and hence demonstrate aerosol delivery of shRab25 as a therapeutic target for lung cancer treatment.

Suppression of tumor growth in lung cancer xenograft model mice by poly(sorbitol-co-PEI)-mediated delivery of osteopontin siRNA.

Small interfering RNA (siRNA)-mediated gene silencing represents a promising strategy for treating diseases such as cancer; however, specific gene silencing requires an effective delivery system to overcome the instability and low transfection efficiency of siRNAs. To address this issue, a polysorbitol-based transporter (PSOT) was prepared by low molecular weight branched polyethylenimine (bPEI) crosslinked with sorbitol diacrylate (SDA). Osteopontin (OPN) gene, which is highly associated with non-small cell lung cancer (NSCLC) was targeted by siRNA therapy using siRNA targeting OPN (siOPN). Characterization study confirmed that PSOT formed compact complexes with siOPN and protected siOPN against degradation by RNase. PSOT/siOPN complexes demonstrated low cytotoxicity and enhanced transfection efficiency in vitro, suggesting that this carrier may be suitable for gene silencing. In the A549 and H460 lung cancer cell lines, PSOT/siOPN complexes demonstrated significant silencing efficiency at both RNA and protein levels. To study in vivo tumor growth suppression, two lung cancer cell-xenograft mouse models were prepared and PSOT/siOPN complexes were delivered into the mice through intravenous injection. The siOPN-treated groups demonstrated significantly reduced OPN expression at both the RNA and protein levels as well as suppression of tumor volume and weight. Taken together, siOPN delivery using PSOT may present an effective and novel therapeutic system for lung cancer treatment.

Galactosylated poly(ethyleneglycol)-lithocholic Acid selectively kills hepatoma cells, while sparing normal liver cells.

Delivering drugs selectively to cancer cells but not to nearby normal cells is a major obstacle in drug therapy. In this study, lithocholic acid (LCA), a potent anti-cancer drug, is converted to two forms of poly(ethyleneglycol) (PEG) conjugates, viz., PEG-LCA (PL) and lactobionic acid (LBA) conjugated PEG-LCA (LPL). The latter form contains a galactose ligand in LBA to target the hepatocytes. Both forms are self-assembled to form nanoparticle formulation, and they have high potency than LCA to kill HepG2 cancer cells, sparing normal LO2 cells. Besides, LPL has high specificity to mouse liver cells in vivo. Western blot results confirm that the cell death is occurred through apoptosis induced by LPL nanoparticles. In conclusion, the induction of apoptosis and cell death is much more efficient with LPL nanoparticles than LCA molecules.