Anti-Cancer and Anti-Proliferative Potential of Cannabidiol: A Cellular and Molecular Perspective.

Cannabinoids, the bioactive compounds found in Cannabis sativa, have been used for medicinal purposes for centuries, with early discoveries dating back to the BC era (BCE). However, the increased recreational use of cannabis has led to a negative perception of its medicinal and food applications, resulting in legal restrictions in many regions worldwide. Recently, cannabinoids, notably Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have gained renewed interest in the medical field due to their anti-cancer properties. These properties include the inhibition of tumour growth and cell invasion, anti-inflammatory effects, and the induction of autophagy and apoptosis. As a result, the use of cannabinoids to treat chemotherapy-associated side effects, like nausea, vomiting, and pain, has increased, and there have been suggestions to implement the large-scale use of cannabinoids in cancer therapy. However, these compounds' cellular and molecular mechanisms of action still need to be fully understood. This review explores the recent evidence of CBD's efficacy as an anti-cancer agent, which is of interest due to its non-psychoactive properties. The current review will also provide an understanding of CBD's common cellular and molecular mechanisms in different cancers. Studies have shown that CBD's anti-cancer activity can be receptor-dependent (CB1, CB2, TRPV, and PPARs) or receptor-independent and can be induced through molecular mechanisms, such as ceramide biosynthesis, the induction of ER stress, and subsequent autophagy and apoptosis. It is projected that these molecular mechanisms will form the basis for the therapeutic applications of CBD. Therefore, it is essential to understand these mechanisms for developing and optimizing pre-clinical CBD-based therapies.

Charting the Cannabis plant chemical space with computational metabolomics.

INTRODUCTION: The chemical classification of Cannabis is typically confined to the cannabinoid content, whilst Cannabis encompasses diverse chemical classes that vary in abundance among all its varieties. Hence, neglecting other chemical classes within Cannabis strains results in a restricted and biased comprehension of elements that may contribute to chemical intricacy and the resultant medicinal qualities of the plant. OBJECTIVES: Thus, herein, we report a computational metabolomics study to elucidate the Cannabis metabolic map beyond the cannabinoids. METHODS: Mass spectrometry-based computational tools were used to mine and evaluate the methanolic leaf and flower extracts of two Cannabis cultivars: Amnesia haze (AMNH) and Royal dutch cheese (RDC). RESULTS: The results revealed the presence of different chemical compound classes including cannabinoids, but extending it to flavonoids and phospholipids at varying distributions across the cultivar plant tissues, where the phenylpropnoid superclass was more abundant in the leaves than in the flowers. Therefore, the two cultivars were differentiated based on the overall chemical content of their plant tissues where AMNH was observed to be more dominant in the flavonoid content while RDC was more dominant in the lipid-like molecules. Additionally, in silico molecular docking studies in combination with biological assay studies indicated the potentially differing anti-cancer properties of the two cultivars resulting from the elucidated chemical profiles. CONCLUSION: These findings highlight distinctive chemical profiles beyond cannabinoids in Cannabis strains. This novel mapping of the metabolomic landscape of Cannabis provides actionable insights into plant biochemistry and justifies selecting certain varieties for medicinal use.

An Integrated Molecular Networking and Docking Approach to Characterize the Metabolome of Helichrysum splendidum and Its Pharmaceutical Potentials.

South Africa is rich in diverse medicinal plants, and it is reported to have over 35% of the global Helichrysum species, many of which are utilized in traditional medicine. Various phytochemical studies have offered valuable insights into the chemistry of Helichrysum plants, hinting at bioactive components that define the medicinal properties of the plant. However, there are still knowledge gaps regarding the size and diversity of the Helichrysum chemical space. As such, continuous efforts are needed to comprehensively characterize the phytochemistry of Helichrysum, which will subsequently contribute to the discovery and exploration of Helichrysum-derived natural products for drug discovery. Thus, reported herein is a computational metabolomics work to comprehensively characterize the metabolic landscape of the medicinal herb Helichrysum splendidum, which is less studied. Metabolites were methanol-extracted and analyzed on a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Spectral data were mined using molecular networking (MN) strategies. The results revealed that the metabolic map of H. splendidum is chemically diverse, with chemical superclasses that include organic polymers, benzenoids, lipid and lipid-like molecules, alkaloids, and derivatives, phenylpropanoids and polyketides. These results point to a vastly rich chemistry with potential bioactivities, and the latter was demonstrated through computationally assessing the binding of selected metabolites with CDK-2 and CCNB1 anti-cancer targets. Molecular docking results showed that flavonoids (luteolin, dihydroquercetin, and isorhamnetin) and terpenoids (tiliroside and silybin) interact strongly with the CDK-2 and CCNB1 targets. Thus, this work suggests that these flavonoid and terpenoid compounds from H. splendidum are potentially anti-cancer agents through their ability to interact with these proteins involved in cancer pathways and progression. As such, these actionable insights are a necessary step for further exploration and translational studies for H. splendidum-derived compounds for drug discovery.

Zooming into the structure-function of RING finger proteins for anti-cancer therapeutic applications.

Cancer is one of the most common and widely diagnosed diseases worldwide. With an increase in prevalence and incidence, many studies in cancer biology have been looking at the role pro-cancer proteins play. One of these proteins is the Really Interesting New Gene (RING), which has been studied extensively due to its structure and functions such as apoptosis, neddylation, and its role in ubiquitination. The RING domain is a cysteine-rich domain known to bind Cysteine and Histidine residues. It also binds two zinc ions that help stabilize the protein in various patterns, often with a 'cross-brace' topology. Different RING finger proteins have been studied and found to have suitable targets for developing anti-cancer therapeutics. These identified candidate proteins include Parkin, COP1, MDM2, BARD1, BRCA-1, PIRH2, c-CBL, SIAH1, RBX1 and RNF8. Inhibiting these candidate proteins provides opportunities for shutting down pathways associated with tumour development and metastasis.

In vitro and in vivo hepatotoxicity study of Afriplex™ GRT through an inflammatory response.

Background: The focus on traditional and complementary medicine for supplementation and treatment of diseases is high. Aspalathus linearis commonly known as Rooibos showed several beneficial effects, this led to the standardized production of a pharmaceutical grade green rooibos extract (Afriplex TM GRT) with enhanced polyphenolic content. The aim of this study was to assess toxicity of Afriplex TM GRT in HepG2/C3A cells and Sprague Dawley rats. Methods: Afriplex GRT TM (0.1, 1, 10, 100, or 1000 µg/mL) in DMSO was added to the media to the final 0.01% DMSO for treatment of HepG2/C3A for 1, 24 and 48 hrs followed by MTT and ATP assays. Sprague Dawley rats were grouped to Control, Afriplex TM GRT treated (10, 100 and 300 mg/kg); and acute (24hrs tetrachloromethane (CCl 4) injected hepatotoxicity control). Serum biochemistry, histology and Western blot analysis on liver were performed. Results: Afriplex TM GRT significantly reduced cell viability at 100 and 1000µg/mL after 48 hrs. Acute CCl 4 treatment significantly increased serum alanine aminotransferase in rats. The highest extract treatment of 300 mg/kg significantly elevated aspartate amino transferase. There was severe macro vesicular in the CCl 4 group whereas mild to moderate micro vesicular steatosis was seen in the 300 mg/kg Afriplex TM GRT treated group. Highest extract treatment significantly reduced NFkB expression on Western blot analysis. Conclusion: The beneficial effects of pharmaceutical grade Afriplex GRT TM are concentration and dosage based. Afriplex GRT TM exerts its beneficial effects via NFkB as demonstrated by the dose dependent reduction of NFkB on Western blot analysis. More work need to be done to explore the exact mechanism that occurs in the NFkB pathway.

Molecular interaction between small nuclear ribonucleoprotein polypeptide G and heat shock protein 70.14: a microscale thermophoresis exposition towards developing anti-cancer drugs.

BACKGROUND: Targeting protein-protein interactions (PPIs) linked to protein quality control (PQC) pathways as potential anti-cancer drug targets have unanimously widened biological insights and the therapeutic potential of PPIs as smart-drug discovery tools in cancer. PPIs between disease-relevant proteins associated with protein homeostasis in PQC pathways have been linked to improved mechanistic understanding associated with conformational abnormalities and impairment, cellular proteotoxicity, induced apoptosis, and pathogenesis in different types of cancers. In this context, PPIs between small nuclear ribonucleoprotein polypeptide G (SNRPG) and heat shock protein 70.14 (Hsp70.14) have attracted attention as potential smart drug discovery tools in cancer diagnostics and therapeutics. Validated evidence of high-quality biological data has shown the presence of the two proteins in different types of cancers including breast cancer. The links between SNRPG and Hsp70.14 in cancer-cell networks remain elusive, overlooked, and uncharacterized. METHODOLOGY: In this study, we explored the interaction between the two oncogenic proteins using the MST-based assays. RESULTS: The results revealed a low KD in the nanomolar concentration range of 2.4673 × 10-7 demonstrating a great affinity for SNRPG binding to Hsp70.14. CONCLUSIONS: The results suggest a possible involvement between the two proteins in hostile tumour microenvironments. Furthermore, these findings offer a different therapeutic perspective that could pave the way for the creation of novel small molecule inhibitors as drugs for the treatment of cancer.

Bioorganometallic Compounds as Novel Drug Targets against Schistosomiasis in Sub-Saharan Africa: An alternative to Praziquantel?

Human schistosomiasis is a disease that mostly plagues the destitute of various tropical and sub-tropical countries, particularly in sub-Saharan Africa (SSA) and South America. It has significant effects on various health and economic-related matters. Globally, the burden of schistosomiasis has been controlled with a single chemotherapeutic drug, praziquantel (PZQ), which has recently demonstrated several clinical issues, including its inability to destroy juvenile schistosome worms and drug resistance because of its extensive use. The use of organometallic moieties in biological and medicinal chemistry has developed greatly and has led to their use in various anti-cancer and anti-infectious agents. The abundance of a range of organometallic compounds that can cause damage to the parasite has received tremendous feedback, with many already at clinical trials. The distinct redox biology of the schistosome parasite is a vulnerable element to the survival of the worm and has steered attempts toward the use of redox-directed bioorganometallic compounds. Disruption of the schistosome redox homeostasis through organometallic ions provides a novel drug target that could be used in overcoming the drawbacks of the mainstream drug and one that could possibly bypass the emergence of drug resistance.

Microscale thermophoresis analysis of the molecular interaction between small nuclear ribonucleoprotein polypeptide G and the RING finger domain of RBBP6 towards anti-cancer drug discovery.

Regulatory core-splicing proteins are now becoming highly promising therapeutic targets for the development of anti-cancer drugs. SNRPG and RBBP6 are two good examples of regulatory core-splicing proteins involved in tumorigenesis and tumor development whose multi-functional role is primarily mediated by protein-protein interactions. Over the years, skepticism abutting from the two onco-proteins has been mounting. Suggestive evidence using yeast 2-hybrid technique observed possible involvement between SNRPG and the RING finger domain of RBBP6. However, the putative interaction remains elusive and yet to be characterized. In this study, we developed the first MST-based assay to confirm the interaction between SNRPG and the RING finger domain of RBBP6. The results demonstrated a strong binding affinity between SNRPG and the RING finger domain of RBBP6 with a KD in the low nanomolar concentration range of 3.1596 nM. The results are congruent with previous findings suggesting possible involvement between the two proteins in cancer-cell networks, thereby providing a new mechanistic insight into the interaction between SNRPG and the RING finger domain of RBBP6. The interaction is therapeutically relevant and represents a great milestone in the anti-cancer drug discovery space. Identification of small molecule inhibitors to modulate the binding affinity between the two proteins would therefore be a major breakthrough in the development of new PPI-focused anti-cancer drugs.

Parasite Survival and Disease Persistence in Cystic Fibrosis, Schistosomiasis and Pathogenic Bacterial Diseases: A Role for Universal Stress Proteins?

Universal stress proteins (USPs) were originally discovered in Escherichia coli over two decades ago and since then their presence has been detected in various organisms that include plants, archaea, metazoans, and bacteria. As their name suggests, they function in a series of various cellular responses in both abiotic and biotic stressful conditions such as oxidative stress, exposure to DNA damaging agents, nutrient starvation, high temperature and acidic stress, among others. Although a highly conserved group of proteins, the molecular and biochemical aspects of their functions are largely evasive. This is concerning, as it was observed that USPs act as essential contributors to the survival/persistence of various infectious pathogens. Their ubiquitous nature in various organisms, as well as their augmentation during conditions of stress, is a clear indication of their direct or indirect importance in providing resilience against such conditions. This paper seeks to clarify what has already been reported in the literature on the proposed mechanism of action of USPs in pathogenic organisms.

Immunological and Biochemical Interplay between Cytokines, Oxidative Stress and Schistosomiasis.

The host-parasite schistosome relationship relies heavily on the interplay between the strategies imposed by the schistosome worm and the defense mechanisms the host uses to counter the line of attack of the parasite. The ultimate goal of the schistosome parasite entails five important steps: evade elimination tactics, survive within the human host, develop into adult forms, propagate in large numbers, and transmit from one host to the next. The aim of the parasitized host on the other hand is either to cure or limit infection. Therefore, it is a battle between two conflicting aspirations. From the host's standpoint, infection accompanies a plethora of immunological consequences; some are set in place to defend the host, while most end up promoting chronic disease, which ultimately crosses paths with oxidative stress and cancer. Understanding these networks provides attractive opportunities for anti-schistosome therapeutic development. Hence, this review discusses the mechanisms by which schistosomes modulate the human immune response with ultimate links to oxidative stress and genetic instability.

Closing the Gap: An Atomistic Structural and Functional Perspective of S. mansoni Universal Stress G4LZI3 Protein in Complex with Phenolic Compounds.

BACKGROUND: For decades, Praziquantel has been the undisputed drug of choice for all schistosome infections, but rising concerns due to the unelucidated mechanism of action of the drug and unavoidable reports of emerging drug resistant strains has necessitated the need for alternative treatment drug. Moreover, current apprehension has been reinforced by total dependence on the drug for treatment hence, the search for novel and effective anti-schistosomal drugs. METHODS: This study made use of bioinformatic tools to determine the structural binding of the Universal G4LZI3 Stress Protein (USP) in complex with ten polyphenol compounds, thereby highlighting the effectiveness of these recently identified 'lead' molecules in the design of novel therapeutics targeted against schistosomiasis. Upregulation of the G4LZI3 USP throughout the schistosome multifaceted developmental cycle sparks interest in its potential role as a druggable target. The integration of in silico tools provides an atomistic perspective into the binding of potential inhibitors to target proteins. This study therefore, implemented the use of Molecular Dynamic (MD) simulations to provide functional and structural insight into key conformational changes upon binding of G4- ZLI3 to these key phenolic compounds. RESULTS: Post-MD analyses revealed unique structural and conformational changes in the G4LZI3 protein in complex with curcumin and catechin respectively. These systems exhibited the highest binding energies, while the major interacting residues conserved in all the complexes provides a route map for structure-based drug design of novel compounds with enhanced inhibitory potency against the G4LZI3 protein. CONCLUSION: This study suggests an alternative approach for the development of anti-schistosomal drugs using natural compounds.

Molecular Context of ADP-ribosylation in Schistosomes for Drug Discovery and Vaccine Development.

Schistosome infection is regarded as one of the most important and neglected tropical diseases associated with poor sanitation. Like other living organisms, schistosomes employ multiple biological processes, of which some are regulated by a post-translational modification called Adenosine Diphosphate-ribosylation (ADP-ribosylation), catalyzed by ADP-ribosyltransferases. ADP-ribosylation is the addition of ADP-ribose moieties from Nicotinamide Adenine Dinucleotide (NAD+) to various targets, which include proteins and nucleotides. It is crucial in biological processes such as DNA repair, apoptosis, carbohydrate metabolism and catabolism. In the absence of a vaccine against schistosomiasis, this becomes a promising pathway in the identification of drug targets against various forms of this infection. The tegument of the worm is an encouraging immunogenic target for anti-schistosomal vaccine development. Vaccinology, molecular modeling and target-based drug discovery strategies have been used for years in drug discovery and for vaccine development. In this paper, we outline ADP-ribosylation and other different approaches to drug discovery and vaccine development against schistosomiasis.

Investigation of the In Vitro Antioxidant Potential Of Polyphenolic-Rich Extract of Artocarpus heterophyllus Lam Stem Bark and Its Antidiabetic Activity In Streptozotocin-Induced Diabetic Rats.

Artocarpus heterophyllus Lam (Moraceae) stem bark has been used locally in managing diabetes mellitus with sparse scientific information. This study investigates the in vitro antioxidant potential of polyphenolic-rich extract of A heterophyllus stem bark as well as its antidiabetic activity in streptozotocin-induced diabetic rats. Fifty male Wistar rats were used with the induction of diabetes by a single intraperitoneal injection of streptozotocin (45 mg/kg body weight) and were orally administered 400 mg/kg free and bound phenols of A heterophyllus stem bark. The animals were sacrificed on the 28th day of the experiment using the cervical dislocation method; antihyperglycemia and anti-inflammatory parameters were subsequently assessed. The polyphenolic extracts demonstrated antioxidant potentials (such as hydrogen peroxide and diphenyl-1-picrylhydrazyl), as well as strong inhibitory activity against amylase and glucosidase. There was a significant (P < .05) increase in glycogen, insulin concentration, pancreatic ß-cell scores (HOMA-ß), antioxidant enzymes and hexokinase activities, as well as glucose transporter concentration in diabetic animals administered the extracts and metformin. Also, a significant (P < .05) reduction in fasting blood glucose, lipid peroxidation, glucose-6-phosphatase, and all anti-inflammatory parameters were observed in diabetic rats administered the extracts and metformin. The extracts demonstrated antidiabetic potential, which may be useful in the management of diabetes mellitus.

In vitro antioxidant and inhibitory activities of polyphenolic-rich extracts of Syzygium cumini (Linn) Skeels leaf on two important enzymes relevant to type II diabetes mellitus.

In this study, the effect of free and bound polyphenolic-rich extract of Syzygium cumini (Linn) Skeels leaf on antioxidant as well as α-amylase and α-glucosidase activities were determined using in vitro model. Polyphenolic-rich extract of Syzygium cumini (Linn) Skeels leaf was prepared accordingly and the capability of the extract to inhibit antioxidants as typified by ferric reducing power (FRAP) and 1,1-diphenyl-2-picryl-hydrazil (DPPH) among other free radicals scavenging abilities were quantified spectrophotometrically, added to this, the activities of (α-amylase and α-glucosidase were also assessed. The bound phenolic extract exhibited more in vitro antioxidant properties as represented by their high radicals scavenging ability in all the free radicals evaluated. Also, the polyphenolic-rich extracts inhibited α-amylase and α-glucosidase, with bound phenolics showing significant (p<0.05) increase in a dose-dependent manner than free phenolics. Therefore, this study suggests the use of Syzygium cumini leaf as a nutraceutical in the management/ control of type II diabetes mellitus patients.

The oncogenic potential of small nuclear ribonucleoprotein polypeptide G: a comprehensive and perspective view.

Small nuclear ribonucleoprotein polypeptide G (SNRPG), often referred to as Smith protein G (SmG), is an indispensable component in the biogenesis of spliceosomal uridyl-rich small nuclear ribonucleoprotein particles (U snRNPs; U1, U2, U4 and U5), which are precursors of both the major and minor spliceosome. SNRPG has attracted significant attention because of its implicated roles in tumorigenesis and tumor development. Suggestive evidence of its varying expression levels has been reported in different types of cancers, which include breast cancer, lung cancer, prostate cancer and colon cancer. The accumulating evidence suggests that the splicing machinery component plays a significant role in the initiation and progression of cancers. SNRPG has a wide interaction network, and its functions are predominantly mediated by protein-protein interactions (PPIs), making it a promising anti-cancer therapeutic target in PPI-focused drug technology. Understanding its roles in tumorigenesis and tumor development is an indispensable arsenal in the development of molecular-targeted therapies. Several antitumor drugs linked to splicing machinery components have been reported in different types of cancers and some have already entered the clinic. However, targeting SNRPG as a drug development tool has been an overlooked and underdeveloped strategy in cancer therapy. In this article, we present a comprehensive and perspective view on the oncogenic potential of SNRPG in PPI-focused drug discovery.

Current Biochemical Applications and Future Prospects of Chlorotoxin in Cancer Diagnostics and Therapeutics.

Chlorotoxin (CTX) is a minute 4 kDa protein made up of 36 amino acid residues, commonly known for its binding affinity to chloride channels and matrix metalloproteinase-2 (MMP-2) of glioma tumors of the spine and brain. This property and the possibility of conjugating this peptide to nanoparticles have enabled its diverse use in various biotechnological and biomedical applications for cancer treatment, such as in tumor imaging and radiotherapy. Because of the fascinating biological properties CTX possesses, elucidating its mechanism of action may hold promise for the development of new and effective therapeutic drugs, as well as more sensitive and highly specific cancer-screening kits. This article therefore reviews the currently known applications of CTX and suggests diverse ways in which it can be applied for the design of improved drugs and diagnostic tools for cancer.

PZQ Therapy: How Close are we in the Development of Effective Alternative Anti-schistosomal Drugs?

Today schistosomiasis, caused mainly by the three major schistosome species (S. mansoni, S. haematobium and S. japonicum), has for many decades and still continues to be on a rapid and swift rise globally, claiming thousands of lives every year and leaving 800 million people at the risk of infection. Due to the high prevalence of this disease and the steady increase in the infection rates, praziquantel (PZQ) remains the only effective drug against this acute disease although it has no effect on the juvenile schistosome parasite. However, no significant approaches have been made in recent years in the discovery of new or alternative drugs and unfortunately, resistance to this drug has been reported in some parts of the world. Therefore, it is imperative to develop a new drug for this debilitating disease. In this review, a brief history of past, present, and new promising anti-schistosomal drugs is presented.

Molecular Application of Aptamers in the Diagnosis and Treatment of Cancer and Communicable Diseases.

Cancer and infectious diseases such as Ebola, HIV, tuberculosis, Zika, hepatitis, measles and human schistosomiasis are serious global health hazards. The increasing annual morbidities and mortalities of these diseases have been blamed on drug resistance and the inefficacy of available diagnostic tools, particularly those which are immunologically-based. Antibody-based tools rely solely on antibody production for diagnosis and for this reason they are the major cause of diagnostic delays. Unfortunately, the control of these diseases depends on early detection and administration of effective treatment therefore any diagnostic delay is a huge challenge to curbing these diseases. Hence, there is a need for alternative diagnostic tools, discovery and development of novel therapeutic agents. Studies have demonstrated that aptamers could potentially offer one of the best solutions to these problems. Aptamers are short sequences of either DNA or RNA molecules, which are identified in vitro through a SELEX process. They are sensitive and bind specifically to target molecules. Their promising features suggest they may serve as better diagnostic agents and can be used as drug carriers for therapeutic purposes. In this article, we review the applications of aptamers in the theranostics of cancer and some infectious diseases.

Structural Studies of Predicted Ligand Binding Sites and Molecular Docking Analysis of Slc2a4 as a Therapeutic Target for the Treatment of Cancer.

Presently, many studies have focused on exploring in silico approaches in the identification and development of alternative therapy for the treatment and management of cancer. Solute carrier family-2-member-4-gene (Slc2a4) which encodes glucose transporter 4 protein (GLUT4), has been identified as a promising therapeutic target for cancer. Though Slc2a4 is known to play a major regulatory role in the pathophysiology of type 2 diabetes, emerging evidence suggests that successful pharmacological inhibition of this protein may lead to the development of a novel drug candidate for the treatment of cancer. In this study, Slc2a4 protein sequence was retrieved and analysed using in silico approaches, and we identified seven putative antimicrobial peptides (AMPs; RAB1-RAB7) as anti-cancer. The structures of the protein and AMPs were modelled using I-TASSER server, and the overall quality of the Slc2a4 model was validated using PROCHECK. Subsequently, the probable motifs and active site of the protein were forecasted. Also, the molecular interaction between the AMPs and Slc2a4 was ascertained using PatchDock. The result revealed that, all the AMPs are good Slc2a4 inhibitors with RAB1 having the highest binding affinity of 12,392 and binding energy of -39.13 kcal/mol. Hence, this study reveals that all the generated AMPs can serve as therapeutic drug in treating cancer by inhibiting Slc2a4 which is responsible for the production of energy for cancer cells during angiogenesis. This is the first report on AMPs as inhibitors of Slc2a4 for the treatment of cancer.

Aspalathin Reverts Doxorubicin-Induced Cardiotoxicity through Increased Autophagy and Decreased Expression of p53/mTOR/p62 Signaling.

Doxorubicin (Dox) is an effective chemotherapeutic agent used in the treatment of various cancers. Its clinical use is often limited due to its potentially fatal cardiotoxic side effect. Increasing evidence indicates that tumour protein p53 (p53), adenosine monophosphate-activated protein kinase (AMPK), nucleoporin p62 (p62), and the mammalian target of rapamycin (mTOR) are critical mediators of Dox-induced apoptosis, and subsequent dysregulation of autophagy. Aspalathin, a polyphenolic dihydrochalcone C-glucoside has been shown to activate AMPK while decreasing the expression of p53. However, the role that aspalathin could play in the inhibition of Dox-induced cardiotoxicity through increased autophagy flux remained unexplored. H9c2 cardiomyocytes and Caov-3 ovarian cancer cells were cultured in Dulbecco's Modified Eagle's medium and treated with or without Dox for five days. Thereafter, cells exposed to 0.2 µM Dox were co-treated with either 20 µM Dexrazozane (Dexra) or 0.2 µM aspalathin (ASP) daily for 5 days. Results obtained showed that ASP mediates its cytoprotective effect in a p53-dependent manner, by increasing the Bcl-2/Bax ratio and decreasing apoptosis. The latter effect was diminished through ASP-induced activation of autophagy-related genes (Atgs) with an associated decrease in p62 through induction of AMPK and Fox01. Furthermore, we showed that ASP was able to potentiate this effect without decreasing the anti-cancer efficacy of Dox, as could be observed in Caov-3 ovarian cancer cells. Taken together, the data presented in this study provides a credible mechanism by which ASP co-treatment could protect the myocardium from Dox-induced cardiotoxicity.