Apoptosis has been considered the main mechanism induced by cancer chemotherapeutic drugs for a long time. This paradigm is currently evolving and changing, as increasing evidence pointed out that antitumor agents could trigger various non-canonical or non-apoptotic cell death types. A considerable number of antitumor drugs derive from natural sources, both in their naturally occurring form or as synthetic derivatives. Therefore, it is not surprising that several natural compounds have been explored for their ability to induce non-canonical cell death. The aim of this review is to highlight the potential antitumor effects of natural products as ferroptosis, necroptosis, or pyroptosis inducers. Natural products have proven to be promising non-canonical cell death inducers, capable of overcoming cancer cells resistance to apoptosis. However, as discussed in this review, they often lack a full characterization of their antitumor activity together with an in-depth investigation of their toxicological profile.

Even if cancer represents a burden for human society, an exhaustive cure has not been discovered yet. Low therapeutic index and resistance to pharmacotherapy are two of the major limits of antitumour treatments. Natural products represent an excellent library of bioactive molecules. Thus, tapping into the natural world may prove useful in identifying new therapeutic options with favourable pharmaco-toxicological profiles. Juglans regia, or common walnut, is a very resilient tree that has inhabited our planet for thousands of years. Many studies correlate walnut consumption to beneficial effects towards several chronic diseases, such as cancer, mainly due to the bioactive molecules stored in different parts of the plant. Among others, polyphenols, quinones, proteins, and essential fatty acids contribute to its pharmacologic activity. The present review aims to offer a comprehensive perspective about the antitumour potential of the most promising compounds stored in this plant, such as juglanin, juglone, and the ellagitannin-metabolites urolithins or deriving from walnut dietary intake. All molecules and a chronic intake of the fruit provide tangible anticancer effects. However, the scarcity of studies on humans does not allow results to be conclusive.

The marine ecosystem, populated by a myriad of animals, plants, and microorganisms, is an inexhaustible reservoir of pharmacologically active molecules. Among the multiple secondary metabolites produced by marine sources, there are anthraquinones and their derivatives. Besides being mainly known to be produced by terrestrial species, even marine organisms and the uncountable kingdom of marine microorganisms biosynthesize anthraquinones. Anthraquinones possess many different biological activities, including a remarkable antitumor activity. However, due to their peculiar chemical structures, anthraquinones are often associated with toxicological issues, even relevant, such as genotoxicity and mutagenicity. The aim of this review is to critically describe the anticancer potential of anthraquinones derived from marine sources and their genotoxic and mutagenic potential. Marine-derived anthraquinones show a promising anticancer potential, although clinical studies are missing. Additionally, an in-depth investigation of their toxicological profile is needed before advocating anthraquinones as a therapeutic armamentarium in the oncological area.

In traditional Indian medicine, the crude drug Hemidesmus indicus root—commonly known as Indian sarsaparilla—is used alone or in poly-herbal preparations for the treatment of a wide range of diseases. The present study focuses on the cancer chemopreventive and therapeutic potential of H. indicus extracts on an acute lymphoblastic leukemia cell line (CCRF-CEM). With this aim in mind, we subjected H. indicus roots to two subsequent extractions (hydro-alcoholic extraction and soxhlet extraction). As DNA damage is an important prerequisite for the induction of mutations/cancer by genotoxic carcinogens, cancer chemoprevention may be achieved by preventing genotoxicity. Through an integrated experimental approach, we explored the genoprotective potential of the soxhlet H. indicus extract against different mutagenic compounds and its cytotoxic, proapoptotic, and cytostatic properties. In our experimental conditions, H. indicus induced a cytotoxic effect involving the activation of both intrinsic and extrinsic apoptotic pathways and blocked the cell cycle in the S phase. Moreover, the antigenotoxicity results showed that the extract was able to mitigate DNA damage, an essential mechanism for its applicability as a chemopreventive agent, via either the modulation of extracellular and intracellular events involved in DNA damage. These data add to the growing body of evidence that H. indicus can represent a noteworthy strategy to target early and late stages of cancer.

In recent years, natural compounds have emerged as inducers of non-canonical cell death. The isothiocyanate sulforaphane (SFN) is a well-known natural anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell-death mechanisms remains poorly investigated. This work aimed to explore the capacity of SFN to induce non-apoptotic cell death modalities. SFN was tested on different acute myeloid leukemia cell lines. The mechanism of cell death was investigated using a multi-parametric approach including fluorescence microscopy, western blotting, and flow cytometry. SFN triggered different cell-death modalities in a dose-dependent manner. At 25 μM, SFN induced caspase-dependent apoptosis and at 50 μM ferroptosis was induced through depletion of glutathione (GSH), decreased GSH peroxidase 4 protein expression, and lipid peroxidation. In contrast, necroptosis was not involved in SFN-induced cell death, as demonstrated by the non-significant increase in phosphorylation of receptor-interacting protein kinase 3 and phosphorylation of the necroptotic effector mixed lineage kinase domain-like pseudokinase. Taken together, our results suggest that the antileukemic activity of SFN can be mediated via both ferroptotic and apoptotic cell death modalities.

The combination of photodynamic therapy with chemotherapy (photochemotherapy, PCT) can lead to additive or synergistic antitumor effects. Usually, two different molecules, a photosensitizer (PS) and a chemotherapeutic drug are used in PCT. Doxorubicin is one of the most successful chemotherapy drugs. Despite its high efficacy, two factors limit its clinical use: severe side effects and the development of chemoresistance. Doxorubicin is a chromophore, able to absorb light in the visible range, making it a potential PS. Here, we exploited the intrinsic photosensitizing properties of doxorubicin to enhance its anticancer activity in leukemia, breast, and epidermoid carcinoma cells, upon irradiation. Light can selectively trigger the local generation of reactive oxygen species (ROS), following photophysical pathways. Doxorubicin showed a concentration-dependent ability to generate peroxides and singlet oxygen upon irradiation. The underlying mechanisms leading to the increase in its cytotoxic activity were intracellular ROS generation and the induction of necrotic cell death. The nuclear localization of doxorubicin represents an added value for its use as a PS. The use of doxorubicin in PCT, simultaneously acting as a chemotherapeutic agent and a PS, may allow (i) an increase in the anticancer effects of the drug, and (ii) a decrease in its dose, and thus, its dose-related adverse effects.