Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed.

Type 2 diabetes mellitus is one of the most common chronic disease worldwide and affects all cross-sections of the society including children, women, youth and adults. Scientific evidence has linked diabetes to higher incidence, accelerated progression and increased aggressiveness of different cancers. Among the different forms of cancer, research has reinforced a link between diabetes and the risk of breast cancer. Some studies have specifically linked diabetes to the highly aggressive, triple negative breast cancers (TNBCs) which do not respond to conventional hormonal/HER2 targeted interventions, have chances of early recurrence, metastasize, tend to be more invasive in nature and develop drug resistance. Commonly used anti-diabetic drugs, such as metformin, have recently gained importance in the treatment of breast cancer due to their proposed anti-cancer properties. Here we discuss the link between diabetes and breast cancer, the metabolic disturbances in diabetes that support the development of breast cancer, the challenges involved and future perspective and directions. We link the three main metabolic disturbances (dyslipidemia, hyperinsulinemia and hyperglycemia) that occur in diabetes to potential aberrant molecular pathways that may lead to the development of an oncogenic phenotype of the breast tissue, thereby leading to acceleration of cell growth, proliferation, migration, inflammation, angiogenesis, EMT and metastasis and inhibition of apoptosis in breast cancer cells. Furthermore, managing diabetes and treating cancer using a combination of anti-diabetic and classical anti-cancer drugs should prove to be more efficient in the treatment diabetes associated cancers.

Metformin, the most widely prescribed anti-diabetic drug, is shown to possess anti-cancer potential in treatment of cancers, including breast cancer; decreases breast cancer risk; and improves overall survival. However, reports suggest that higher glucose concentrations may negatively impact the anti-cancer efficacy of metformin. Therefore, we examined the anti-cancer potential of metformin in triple-negative breast cancer cells (TNBCs) exposed to different glucose (25 mM, 5.5 mM and zero glucose/glucose-starved) conditions. Our data indicates that a high glucose (25 mM) concentration (mimicking diabetes) significantly abrogated the effect of metformin on cell proliferation, cell death and cell cycle arrest in addition to loss of efficacy in inhibition of the mTOR pathway, a key metabolic pathway in TNBC cells. The mTOR pathway is activated in TNBCs compared to other subtypes of breast cancer, regulates the synthesis of proteins that are critical for the growth and survival of cancer cells and its activation is correlated to poor outcomes among TNBC patients, while also contributing to metastatic progression and development of resistance to chemotherapy/radiotherapy. Our studies were performed in two different types of TNBCs, MDA-MB-231 cells (mesenchymal stem cell-like (MSL)) and MDA-MB-468 (basal like-1 (BL-1)). Interestingly, lower concentrations of metformin (50, 100, 250, and 500 μM) significantly increased cell proliferation in 25 mM glucose exposed MDA-MB-231 cells, an effect which was not observed in MDA-MB-468 cells, indicating that the effective concentration of metformin when used as anti-cancer drug in TNBCs may have to be determined based on cell type and blood glucose concentration. Our data indicates that metformin treatment was most effective under zero glucose/glucose-starved conditions in MDA-MB-468 with a significant increase in the apoptotic population (62.3 ± 1.5%; p-value < 0.01). Under 5.5 mM glucose conditions in both MDA-MB-231 and MDA-MB-468 cells our data showed reduced viability of 73.56 ± 2.53%; p-value < 0.05 and 70.49 ± 1.68%; p-value < 0.001, respectively, along with a significant increase in apoptotic populations of both cell types. Furthermore, metformin (2 mM) inhibited the mTOR pathway and its downstream components under zero glucose/glucose-starved conditions indicating that using metformin in combination with agents that inhibit the glycolytic pathway should be more beneficial for the treatment of triple-negative breast cancers in diabetic individuals.

Chili has culinary as well as medical importance. Studies in humans, using a wide range of doses of chili intake (varying from a single meal to a continuous uptake for up to 12 weeks), concluded that it facilitates weight loss. In regard to this, the main targets of chili are fat metabolism, energy expenditure, and thermogenesis. To induce weight loss, the active substance of chili, capsaicin, activates Transient Receptor Potential Cation Channel sub-family V member 1 (TRPV1) channels) receptors causing an increase in intracellular calcium levels and triggering the sympathetic nervous system. Apart from TRPV1, chili directly reduces energy expenditure by activating Brown Adipose Tissue. Weight loss by chili is also the result of an improved control of insulin, which supports weight management and has positive effects for treatment for diseases like obesity, diabetes and cardiovascular disorders. This review summarizes the major pathways by which chili contributes to ameliorating parameters that help weight management and how the consumption of chili can help in accelerating weight loss through dietary modifications.

Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum complexes (e.g. cisplatin (CDDP), carboplatin), DNA alkylating agents, and topoisomerase I inhibitors (e.g. topotecan (TOPO)). Despite aggressive treatment, NB may become resistant to chemotherapy. We investigated whether CDDP and TOPO treatment of NB cells interacts with the expression and function of proteins involved in regulating calcium signaling. Human neuroblastoma cell lines SH-SY5Y, IMR-32 and NLF were used to investigate the effects of CDDP and TOPO on cell viability, apoptosis, calcium homeostasis, and expression of selected proteins regulating intracellular calcium concentration ([Ca2+]i). In addition, the impact of pharmacological inhibition of [Ca2+]i-regulating proteins on neuroblastoma cell survival was studied. Treatment of neuroblastoma cells with increasing concentrations of CDDP (0.1−10 μM) or TOPO (0.1 nM−1 μM) induced cytotoxicity and increased apoptosis in a concentration- and time-dependent manner. Both drugs increased [Ca2+]i over time. Treatment with CDDP or TOPO also modified mRNA expression of selected genes encoding [Ca2+]i-regulating proteins. Differentially regulated genes included S100A6, ITPR1, ITPR3, RYR1 and RYR3. With FACS and confocal laser scanning microscopy experiments we validated their differential expression at the protein level. Importantly, treatment of neuroblastoma cells with pharmacological modulators of [Ca2+]i-regulating proteins in combination with CDDP or TOPO increased cytotoxicity. Thus, our results confirm an important role of calcium signaling in the response of neuroblastoma cells to chemotherapy and suggest [Ca2+]i modulation as a promising strategy for adjunctive treatment.