Here, we wish to propose a new systematic approach to cancer therapy, based on the targeting of mitochondrial metabolism, especially in cancer stem cells (CSCs). In the future, we envision that anti-mitochondrial therapy would ultimately be practiced as an add-on to more conventional therapy, largely for the prevention of tumor recurrence and cancer metastasis. This mitochondrial based oncology platform would require a panel of FDA-approved therapeutics (e.g. Doxycycline) that can safely be used to inhibit mitochondrial OXPHOS and/or biogenesis in CSCs. In addition, new therapeutics that target mitochondria could also be developed, to optimize their ability to eradicate CSCs. Finally, in this context, mitochondrial-based biomarkers (i.e. “Mito-signatures”) could be utilized as companion diagnostics, to identify high-risk cancer patients at diagnosis, facilitating the early detection of tumor recurrence and the prevention of treatment failure. In summary, we suggest that new clinical trials are warranted to test and possibly implement this emerging treatment strategy, in a variety of human cancer types. This general approach, using FDA-approved antibiotics to target mitochondria, was effective in killing CSCs originating from many different cancer types, including DCIS, breast (ER(+) and ER(-)), prostate, ovarian, lung and pancreatic cancers, as well as melanoma and glioblastoma, among others. Thus, we propose the term MITO-ONC-RX, to describe this anti-mitochondrial platform for targeting CSCs. The use of re-purposed FDA-approved drugs will undoubtedly help to accelerate the clinical evaluation of this approach, as these drugs can move directly into Phase II clinical trials, saving considerable amounts of time (10–15 y) and billions in financial resources.

Research on the energy metabolism of cancer cells is becoming a central element in oncology, and in recent decades, it has allowed us to better understand the mechanisms underlying the onset and chemoresistance of oncological pathologies. Mitochondrial bioenergetic processes, in particular, have proven to be fundamental for the survival of tumor stem cells (CSC), a subpopulation of tumor cells responsible for tumor recurrence, the onset of metastasis, and the failure of conventional anticancer therapies. Over the years, numerous natural products, in particular flavonoids, widely distributed in the plant kingdom, have been shown to interfere with tumor bioenergetics, demonstrating promising antitumor effects. Herein, the anticancer potential of Licoflavanone, a flavanone isolated from the leaves of G. glabra, was explored for the first time in breast cancer cells. The results obtained highlighted a marked antitumor activity that proved to be greater than that mediated by Glabranin or Pinocembrin, flavanones isolated from the same plant matrix. Furthermore, the investigation of Licoflavanone’s effects on breast cancer energy metabolism highlighted the inhibitory activity of this natural product on tumor bioenergetics, a mechanism that could underlie its ability to reduce tumor proliferation, invasiveness, and stemness.

Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype lacking effective targeted therapies, is considered to feature a unique cellular microenvironment with high infiltration of tumor-associated macrophages (TAM), which contribute to worsening breast cancer patient outcomes. Previous studies have shown the antitumoral actions of the dietary omega-3 docosahexaenoic acid (DHA) in both tumor epithelial and stromal components of the breast cancer microenvironment. Particularly in breast cancer cells, DHA can be converted into its conjugate with ethanolamine, DHEA, leading to a more effective anti-oncogenic activity of the parent compound in estrogen receptor-positive breast cancer cells. Here, we investigated the ability of DHEA to attenuate the malignant phenotype of MDA-MB-231 and MDA-MB-436 TNBC cell lines, which in turn influenced TAM behaviors. Our findings revealed that DHEA reduced the viability of TNBC cells in a concentration-dependent manner and compromised cell migration and invasion. Interestingly, DHEA inhibited oxygen consumption and extracellular acidification rates, reducing respiration and the glycolytic reserve in both cell lines. In a co-culture system, TNBC cells exposed to DHEA suppressed recruitment of human THP-1 cells, reduced their viability, and the expression of genes associated with TAM phenotype. Interestingly, we unraveled that the effects of DHEA in TNCB cells were mediated by reduced C-C motif chemokine ligand 5 (CCL5) expression and secretion affecting macrophage recruitment. Overall, our data, shedding new light on the antitumoral effects of DHA ethanolamine-conjugated, address this compound as a promising option in the treatment of TNBC patients.

In this study, a smart hybrid liposome system was achieved combining a self-assembling biopolymer conjugate (human serum albumin-hyaluronic acid) with targeting and redox-responsive activity with dioleoyl phosphatidylethanolamine, a fusogenic phospholipid. The obtained hybrid liposomal structures were found to possess suitable physicochemical properties for cancer therapy application, with mean size of 65 nm, negative surface charge (-27 mV) and the ability to efficiently encapsulate Doxorubicin in the inner liposomal core with high efficiency. The drug loaded hybrid liposomes (DOX@HBLs) were able to trigger the drug release under simulated acidic and redox conditions of the tumor environment, whereas the biological characterization demonstrated the safety and the selectivity of the formulation, able to target the cancer cells (toxicity similar to that of the free drug) while sparing the healthy cells (viability > 90 % in all cases). Furthermore, compared to free drug, DOX@HBLs were able to reduce cell motility, impair metabolic pathways essential for cancer progression, and effectively inhibit spheroid formation (by almost 50 % after 20 days incubation) in both Estrogen Receptor-positive and Triple Negative Breast Cancer cells, demonstrating their high potential as unconventional drug delivery vectors in cancer therapy.

Dyslipidemia is a lipid metabolism disorder associated with the loss of the physiological homeostasis that ensures safe levels of lipids in the organism. This metabolic disorder can trigger pathological conditions such as atherosclerosis and cardiovascular diseases. In this regard, statins currently represent the main pharmacological therapy, but their contraindications and side effects limit their use. This is stimulating the search for new therapeutic strategies. In this work, we investigated in HepG2 cells the hypolipidemic potential of a picrocrocin-enriched fraction, analyzed by high-resolution ¹H NMR and obtained from a saffron extract, the stigmas of Crocus sativus L., a precious spice that has already displayed interesting biological properties. Spectrophotometric assays, as well as expression level of the main enzymes involved in lipid metabolism, have highlighted the interesting hypolipidemic effects of this natural compound; they seem to be exerted through a non-statin-like mechanism. Overall, this work provides new insights into the metabolic effects of picrocrocin, thus confirming the biological potential of saffron and paving the way for in vivo studies that could validate this spice or its phytocomplexes as useful adjuvants in balancing blood lipid homeostasis.