The potential of gossypol and of its R-(−)-enantiomer (R-(−)-gossypol acetic acid, AT-101), has been evaluated for treatment of cancer as an independent agent and in combination with standard chemo-radiation-therapies, respectively. This review assesses the evidence for safety and clinical effectiveness of oral gossypol/AT-101 in treating various types of cancer. The databases PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov were examined. Phase I and II trials as well as single arm and randomized trials were included in this review. Results were screened to determine if they met inclusion criteria and then summarized using a narrative approach. A total of 17 trials involving 759 patients met the inclusion criteria. Overall, orally applied gossypol/AT-101 at low doses (30 mg daily or lower) was determined as well tolerable either as monotherapy or in combination with chemo-radiation. Adverse events should be strictly monitored and were successfully managed by dose-reduction or treating symptoms. There are four randomized trials, two performed in patients with advanced non-small cell lung cancer, one in subjects with head and neck cancer, and one in patients with metastatic castration-resistant prostate cancer. Thereby, standard chemotherapy (either docetaxel (two trials) or docetaxel plus cisplatin or docetaxel plus prednisone) was tested with and without AT-101. Within these trials, a potential benefit was observed in high-risk patients or in some patients with prolongation in progression-free survival or in overall survival. Strikingly, the most recent clinical trial combined low dose AT-101 with docetaxel, fluorouracil, and radiation, achieving complete responses in 11 of 13 patients with gastroesophageal carcinoma (median duration of 12 months) and a median progression-free survival of 52 months. The promising results shown in subsets of patients supports the need of further specification of AT-101 sensitive cancers as well as for the establishment of effective AT-101-based therapy. In addition, the lowest recommended dose of gossypol and its precise toxicity profile need to be confirmed in further studies. Randomized placebo-controlled trials should be performed to validate these data in large cohorts.

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as ‘hidden hunger’), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.

Cancer is the second leading cause of death worldwide and is expected to increase by one-third over the next two decades, in parallel with the growing proportion of the elderly population. Treatment and control of cancer incidence is a global issue. Since there is no clear way to prevent or cure this deadly malignancy, diagnostic, predictive, and prognostic markers for oncological diseases are of great therapeutic value. Minerals and trace elements are important micronutrients for normal physiological function of the body. They are abundant in natural food sources and are regularly included in dietary supplements whereas highly processed industrial food often contains reduced or altered amounts of them. In modern society, the daily intake, storage pools, and homeostasis of these micronutrients are dependent on certain dietary habits and can be thrown out of balance by malignancies. The current work summarizes the data on minerals and trace elements associated with abnormal accumulation or depletion states in tumor patients and discusses their value as potential tumor-associated biomarkers that could be introduced into cancer therapy.

Milk and dairy products, especially from cow’s milk, play a major role in the daily human diet. It is therefore hardly surprising that the subject of milk is being extensively researched and that many effects of individual milk components have been characterized as a result. With the wealth of results available today, the influence of milk on the development of various types of cancer and, in particular, its often protective effects have been shown both in vitro and in vivo and in the evaluation of large-scale cohort and case-control studies. Various caseins, diverse whey proteins such as α-lactalbumin (α-LA), bovine α-lactalbumin made lethal to tumor cells (BAMLET), β-lactoglobulin (β-LG), or bovine serum albumin (BSA), and numerous milk fat components, such as conjugated linoleic acid (CLA), milk fat globule membrane (MFGM), or butyrate, as well as calcium and other protein components such as lactoferrin (Lf), lactoferricin (Lfcin), and casomorphines, show antitumor or cytotoxic effects on cells from different tumor entities. With regard to a balanced and health-promoting diet, milk consumption plays a major role in a global context. This work provides an overview of what is known about the antitumoral properties of proteins derived from cow’s milk and their modes of action.

Resveratrol, a natural plant phytoalexin, is produced in response to fungal infection or− UV irradiation. It exists as an isomeric pair with cis- and trans-conformation. Whereas multiple physiological effects of the trans-form, including a pronounced anti-tumoral activity, are nowadays elucidated, much less knowledge exists concerning the cis-isomer. In our work, we analyzed the antiproliferative and cytotoxic properties of cis-resveratrol in four different human tumor entities in direct comparison to trans-resveratrol. We used human cell lines as tumor models for hepatocellular carcinoma (HCC; HepG2, Hep3B), colon carcinoma (HCT-116, HCT-116/p53^(−/−)), pancreatic carcinoma (Capan-2, MiaPaCa-2), and renal cell carcinoma (A498, SN12C). Increased cytotoxicity in all investigated tumor cells was observed for the trans-isomer. To verify possible effects of the tumor suppressor p53 on resveratrol-induced cell death, we used wild type and p53-deleted or -mutated cell lines for every tested tumor entity. Applying viability and cytotoxicity assays, we demonstrated a differential, dose-dependent sensitivity towards cis- or trans-resveratrol among the respective tumor types.

Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5–50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity.