methyl-jasmonate and Breast-Neoplasms

Autocrine motility factor (AMF) stimulates the motility of cancer cells via an autocrine route and has been implicated in tumor progression and metastasis. Overexpression of AMF is correlated with the aggressive nature of breast cancer and is negatively associated with clinical outcomes. In contrast, AMF also has the ability to suppress cancer cells. In this study, AMFs from different cancer cells were demonstrated to have suppressive activity against MCF-7 and MDA-MB-231 breast cancer cells. In a growth and colony formation assay, AMF from AsPC-1 pancreatic cancer cells (ASPC-1:AMF) was determined to be more suppressive compared to other AMFs. It was also demonstrated that AsPC-1:AMF could arrest breast cancer cells at the G0/G1 cell cycle phase. Quantified by Western blot analysis, AsPC-1:AMF lowered levels of the AMF receptor (AMFR) and G-protein-coupled estrogen receptor (GPER), concomitantly regulating the activation of the AKT and ERK signaling pathways. JAK/STAT activation was also decreased. These results were found in estrogen receptor (ER)-positive MCF-7 cells but not in triple-negative MDA-MB-231 cells, suggesting that AsPC-1:AMF could work through multiple pathways led to apoptosis. More importantly, AsPC-1:AMF and methyl jasmonate (MJ) cooperatively and synergistically acted against breast cancer cells. Thus, AMF alone or along with MJ may be a promising breast cancer treatment option.

Topics: Acetates; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cloning, Molecular; Cyclopentanes; Cytokines; Down-Regulation; Drug Synergism; Female; Glucose-6-Phosphate Isomerase; Humans; MCF-7 Cells; Molecular Targeted Therapy; Oxylipins; Receptors, Autocrine Motility Factor; Recombinant Proteins; Signal Transduction; Tumor Stem Cell Assay

Cancer cells apply the Warburg pathway to meet their increased metabolic demands caused by their rapid growth and proliferation and also creates an acidic environment to promote cancer cell invasion. 3-bromopyruvate (3-BrP) as an anti-cancer agent disrupts glycolytic pathway. Moreover, one of the mechanism of actions of Methyl Jasmonate (MJ) is interference in glycolysis. Hence, the aim of this study was to evaluate MJ and 3-BrP interaction. MTT assay was used to determine IC50 and synergistic concentrations. Combination index was applied to evaluate the drug- drug interaction. Human tumor xenograft breast cancer mice was used to evaluate drug efficacy in vivo. Tumor size was considered as a drug efficacy criterion. In addition to drug efficacy, probable side effects of these drugs including hepatotoxicity, renal failure, immunotoxicity, and losing weight were evaluated. Serum alanine aminotransferase and aspartate aminotransferase for hepatotoxicity, serum urea and creatinine level for the possibility of renal failure and changes in body weight were measured to evaluate drug toxicity. IL10 and TGFβ secretion in supernatant of isolated splenocytes from treated mice were assessed to check immunotoxicity. 3-BrP synergistically augmented the efficacy of MJ in the specific concentrations. This polytherapy was more effective than monotherapy of 3-BrP, MJ, and also surprisingly cyclophosphamide as a routine treatment for breast cancer in the tumor bearing mice. These results have been shown by decrease in tumor volume and increase of tumor growth inhibition percentage. This combination therapy didn't have any noticeable side effects on kidney, liver, and immune system and body weight.

Topics: Acetates; Affinity Labels; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cyclopentanes; Disease Models, Animal; Female; Mice; Oxylipins; Plant Growth Regulators; Pyruvates; Xenograft Model Antitumor Assays

Methyl jasmonate (MJ), a plant-derived stress hormone, has been shown to be a promising anti-cancer agent with high selectivity toward cancerous cells. The aim of the present study was to design a MJ loaded nanoemulsion (NE) to overcome the low MJ water solubility and also improve its anti-cancer efficiency. Box-Behnken design (BBD) was employed to optimize the composition effect of three independent manufacturing variables on two responses including average droplet size and poly dispersity index (PDI). ANOVA analysis indicated that both of the studied responses were well fitted by resultant quadratic models with the coefficient of determinations (R2) 0.994 and 0.975, respectively. The actual average droplet size 75.06 nm and PDI 0.017 obtained for the optimum MJNE was in good agreement with those values predicted with numerical optimization. Physicochemical characterization indicated that the optimum MJNE was transparent, isotropic, spherical and sterically stabilized. MTT assay indicated that MJNE was more efficacious in killing cancer cells than MJ solution. Cell cycle analysis revealed that MJNE induced a stronger sub-G1 arrest than MJ solution. A considerable absence of toxicity was achieved for MJNE and blank NE in HUVEC normal cells. These results may provide strong support to develop a NE delivery system as a promising carrier for improving the safety and anti-cancer efficacy of MJ.

Topics: Acetates; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Cycle; Chemistry, Pharmaceutical; Cyclopentanes; Drug Delivery Systems; Emulsions; Human Umbilical Vein Endothelial Cells; Humans; MCF-7 Cells; Nanoparticles; Oxylipins; Particle Size; Solubility

Breast cancer is the second leading cause of cancer deaths among women in the United States. Several treatment options exist, with different side effects. To alleviate the side effects, several research groups have studied chemotherapeutic effects of plant compounds on cancer cells. These could be used as an alternative treatment option either alone or in combination with other chemotherapeutic drugs. The aim of this study was to evaluate the activity of a combination of perillyl alcohol (POH), methyl jasmonate (MJ) with cisplatin to define the most effective schedule and to investigate the mechanism of action in breast cancer cells. POH and MJ treatment (20% decrease in cell viability concentration) enhanced the cytotoxicity for subsequent exposure to cisplatin in MDA-MB-435 and MDA-MB-231 cells. Combination treatment of POH and MJ blocked cells at the G0/G1 phase of the cell cycle and the addition of cisplatin forced the cells to progress through the cell cycle and induced apoptosis. Apoptotic mechanistic studies indicated that POH and MJ treatment activated tumor necrosis factor receptor 1 and this was further increased by the addition of cisplatin. It was also found that mitochondrial membrane potential decreased with POH and MJ treatment; this effect was further enhanced by cisplatin treatment. These findings contributed to a better understanding of molecular mechanism of apoptosis in combination treatment of POH, MJ, and cisplatin. Results also showed that the combination treatment of three drugs is more effective than single drug alone or two drugs together.

Topics: Acetates; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Culture Techniques; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Cyclopentanes; Drug Synergism; Female; Flow Cytometry; Humans; Membrane Potential, Mitochondrial; Monoterpenes; Oxylipins; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha; Tumor Stem Cell Assay

In recent years, studies with plant compounds have shown both chemotherapeutic and chemopreventive properties. This study with plant stress hormones (jasmonates) showed growth inhibitory effects in breast cancer cells. cis-Jasmone and methyl jasmonate (MJ) inhibited the long-term proliferation of MDA-MB-435 and MCF-7 cells. Cell cycle analysis showed G0/G1 and S-phase arrest with increasing apoptotic population. Cellular signaling studies with MJ showed decreased membrane fluidity and activation of extrinsic and intrinsic apoptotic pathways. Specifically in extrinsic apoptotic pathway increased expression of TNF receptor 1, activation of mitogen-activated protein kinase and caspase-8 was observed. MJ also decreased the mitochondrial membrane potential and activated caspase-3 in breast cancer cells. In conclusion our results revealed novel-signaling mechanism of MJ in breast cancer cells, indicating that MJ could have potential applications for chemotherapeutic purposes.

Topics: Acetates; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Caspase 3; Caspase 8; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclopentanes; DNA Fragmentation; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Membrane Fluidity; Membrane Potentials; Mitogen-Activated Protein Kinases; Oxylipins; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; Tumor Stem Cell Assay