Therapeutic coordination polymers: tailoring drug release through metal-ligand interactions.

Developing tunable materials which exhibit sustained drug release is a considerable challenge. Herein, we report the concept of Therapeutic Coordination Polymers (TCPs); non-porous coordination polymers constructed from biocompatible components which demonstrate tunable zero-order drug release kinetics upon degradation of metal-ligand bonds. TCPs were constructed from three principal components: (i) a cationic metal center (M = Mg2+, Mn2+, Zn2+, or Cu2+); (ii) an anionic drug (Diclofenac); and (iii) an alkyl bis-imidazole organic ligand which behaves as a "linker" between metal centers. Most drug-release materials, such as amorphous polymer dispersions, or metal-organic frameworks rely on a diffusion-based mechanism for drug release, but the degradation-controlled release of drugs from non-porous one-periodic coordination polymers has been largely unexplored. TCPs described herein exhibit a high wt% of pharmaceutical (>62%), tailorable zero-order drug release rate kinetics which span over three orders of magnitude, and stimuli-responsive drug release behavior making them well suited for extended drug-release applications.

Autophagy Inhibition via Hydroxychloroquine or 3-Methyladenine Enhances Chemotherapy-Induced Apoptosis in Neuro-Blastoma and Glioblastoma.

Neuroblastoma is the most common tumour in children under 1 year old, accounting for 12-15% of childhood cancer deaths. Although current treatments are relatively efficacious against this cancer, associated adverse effects could be detrimental to growth and development. In contrast, glioblastoma accounts for 52% of brain tumours and has an extremely poor prognosis. Current chemotherapeutics include temozolomide, which has numerous negative side-effects and a low-effective rate. Previous studies have shown the manipulation of autophagy to be a promising method for targeting cancers, including glioblastoma. We sought to determine the effects of autophagic alterations in combination with current chemotherapies in both neuroblastoma and glioblastoma. Supplementing cisplatin or temozolomide with autophagy activator rapamycin stabilized cancer cell mitochondria, despite having little effect on apoptosis or oxidative stress. Autophagy inhibition via 3-methyladenine or hydroxychloroquine alongside standard chemotherapies enhanced apoptosis and oxidative stress, with 3-methyladenine also disrupting mitochondrial health. Importantly, combining hydroxychloroquine with 0.5 µM cisplatin or 50 µg/mL temozolomide was as or more effective than 2 µM cisplatin or 100 µg/mL temozolomide alone. Analyzing these interesting results, a combined treatment of autophagy inhibitor with a standard chemotherapeutic agent could help to improve patient prognosis and reduce chemotherapy doses and their associated side-effects.

Ubisol-Q10, a Nanomicellar and Water-Dispersible Formulation of Coenzyme-Q10 as a Potential Treatment for Alzheimer's and Parkinson's Disease.

The world continues a desperate search for therapies that could bring hope and relief to millions suffering from progressive neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). With oxidative stress thought to be a core stressor, interests have long been focused on applying redox therapies including coenzyme-Q10. Therapeutic use has failed to show efficacy in human clinical trials due to poor bioavailability of this lipophilic compound. A nanomicellar, water-dispersible formulation of coenzyme-Q10, Ubisol-Q10, has been developed by combining coenzyme-Q10 with an amphiphilic, self-emulsifying molecule of polyoxyethanyl α-tocopheryl sebacate (derivatized vitamin E). This discovery made possible, for the first time, a proper assessment of the true therapeutic value of coenzyme-Q10. Micromolar concentrations of Ubisol-Q10 show unprecedented neuroprotection against neurotoxin exposure in in vitro and in vivo models of neurodegeneration and was extremely effective when delivered either prior to, at the time of, and most significantly, post-neurotoxin exposure. These findings indicate a possible way forward for clinical development due to effective doses well within Federal Drug Administration guidelines. Ubisol-Q10 is a potent mobilizer of astroglia, antioxidant, senescence preventer, autophagy activator, anti-inflammatory, and mitochondrial stabilizer. Here we summarize the work with oil-soluble coenzyme-Q10, its limitations, and focus mainly on efficacy of water-soluble coenzyme-Q10 in neurodegeneration.

Combined Ubisol-Q10 and Ashwagandha Root Extract Target Multiple Biochemical Mechanisms and Reduces Neurodegeneration in a Paraquat-Induced Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by progressive neurodegeneration in the substantia nigra (SN) region resulting in loss of movement coordination. Current therapies only provide symptomatic relief, and there is no agent to halt the progression of PD. Previously, Ubisol-Q10, a water-soluble formulation of coenzyme-Q10, and ethanolic root extract of ashwagandha (ASH) have been shown to inhibit PD pathology in rodent models when used alone. Here, we evaluated the neuroprotective efficacy of oral administration of ASH and Ubisol-Q10 alone and in combination in a paraquat-induced PD rat model. The combined treatment resulted in better-preserved neuron morphology compared to Ubsiol-Q10 or ASH alone. The combination treatment enhanced activation of pro-survival astroglia and inhibited pro-inflammatory microglia. While anti-oxidative effects were seen with both agents, Ubisol-Q10 activated autophagy, whereas ashwagandha showed a better anti-inflammatory response. Thus, the combined treatment caused inhibition of oxidative stress, autophagy activation, inhibition of pro-inflammatory microglia, and activation of pro-survival astroglia. Consequently, paraquat (PQ)-treated rats given the combination treatment in drinking water did not show motor impairment. Based on these interesting observations, the combined treatment containing two well-tolerated natural compounds could be a more effective strategy to halt the progression of PD.

Current Advancements and Novel Strategies in the Treatment of Metastatic Melanoma.

Melanoma is the deadliest form of skin cancer in the world with a growing incidence in North America. Contemporary treatments for melanoma include surgical resection, chemotherapy, and radiotherapy. However, apart from resection in early melanoma, the prognosis of patients using these treatments is typically poor. In the past decade, there have been significant advancements in melanoma therapies. Immunotherapies such as ipilimumab and targeted therapies such as vemurafenib have emerged as a promising option for patients as seen in both scientific and clinical research. Furthermore, combination therapies are starting to be administered in the form of polychemotherapy, polyimmunotherapy, and biochemotherapy, of which some have shown promising outcomes in relative efficacy and safety due to their multiple targets. Alongside these treatments, new research has been conducted into the evidence-based use of natural health products (NHPs) and natural compounds (NCs) on melanoma which may provide a long-term and non-toxic form of complementary therapy. Nevertheless, there is a limited consolidation of the research conducted in emerging melanoma treatments which may be useful for researchers and clinicians. Thus, this review attempts to evaluate the therapeutic efficacy of current advancements in metastatic melanoma treatment by surveying new research into the molecular and cellular basis of treatments along with their clinical efficacy. In addition, this review aims to elucidate novel strategies that are currently being used and have the potential to be used in the future.

Natural Health Products (NHP's) and Natural Compounds as Therapeutic Agents for the Treatment of Cancer; Mechanisms of Anti-Cancer Activity of Natural Compounds and Overall Trends.

Most cancer therapeutics, such as tubulin-targeting chemotherapy drugs, cause cytotoxic, non-selective effects. These harmful side-effects drastically reduce the cancer patient's quality of life. Recently, researchers have focused their efforts on studying natural health products (NHP's) which have demonstrated the ability to selectively target cancer cells in cellular and animal models. However, the major hurdle of clinical validation remains. NHP's warrant further clinical investigation as a therapeutic option since they exhibit low toxicity, while retaining a selective effect. Additionally, they can sensitize cancerous cells to chemotherapy, which enhances the efficacy of chemotherapeutic drugs, indicating that they can be utilized as supplemental therapy. An additional area for further research is the investigation of drug-drug interactions between NHP's and chemotherapeutics. The objectives of this review are to report the most recent results from the field of anticancer NHP research, and to highlight the most recent advancements in possible supplemental therapeutic options.

Lemongrass Extract Possesses Potent Anticancer Activity Against Human Colon Cancers, Inhibits Tumorigenesis, Enhances Efficacy of FOLFOX, and Reduces Its Adverse Effects.

Current chemotherapeutics for metastatic colorectal cancers have limited success and are extremely toxic due to nonselective targeting. Some natural extracts have been traditionally taken and have shown anticancer activity. These extracts have multiple phytochemicals that can target different pathways selectively in cancer cells. We have shown previously that lemongrass (Cymbopogon citratus) extract is effective at inducing cell death in human lymphomas. However, the efficacy of lemongrass extract on human colorectal cancer has not been investigated. Furthermore, its interactions with current chemotherapies for colon cancer is unknown. In this article, we report the anticancer effects of ethanolic lemongrass extract in colorectal cancer models, and importantly, its interactions with FOLFOX and Taxol. Lemongrass extract induced apoptosis in colon cancer cells in a time and dose-dependent manner without harming healthy cells in vitro. Oral administration of lemongrass extract was well tolerated and effective at inhibiting colon cancer xenograft growth in mice. It enhanced the anticancer efficacy of FOLFOX and, interestingly, inhibited FOLFOX-related weight loss in animals given the combination treatment. Furthermore, feeding lemongrass extract to APCmin/+ transgenic mice led to the reduction of intestinal tumors, indicating its preventative potential. Therefore, this natural extract has potential to be developed as a supplemental treatment for colorectal cancer.

Dandelion Root and Lemongrass Extracts Induce Apoptosis, Enhance Chemotherapeutic Efficacy, and Reduce Tumour Xenograft Growth In Vivo in Prostate Cancer.

Many conventional chemotherapies have indicated side effects due to a lack of treatment specificity and are thus not suitable for long-term usage. Natural health products are well-tolerated and safe for consumption, and some have pharmaceutical uses particularly for their anticancer effects. We have previously reported the anticancer efficacy of dandelion (Taraxacum officinale) root and lemongrass (Cymbopogon citratus) extracts. However, their efficacy on prostate cancer and their interactions with standard chemotherapeutics have not been studied to determine if they will be suitable for adjuvant therapies. If successful, these extracts could potentially be used in conjunction with chemotherapeutics to minimize the risk of drug-related toxicity and enhance the efficacy of the treatment. We have demonstrated that both dandelion root extract (DRE) and lemongrass extract (LGE) exhibit selective anticancer activity. Importantly, DRE and LGE addition to the chemotherapeutics taxol and mitoxantrone was determined to enhance the induction of apoptosis when compared to individual chemotherapy treatment alone. Further, DRE and LGE were able to significantly reduce the tumour burden in prostate cancer xenograft models when administered orally, while also being well-tolerated. Thus, the implementation of these well-tolerated extracts in adjuvant therapies could be a selective and efficacious approach to prostate cancer treatment.

Evaluating the Anti-cancer Efficacy of a Synthetic Curcumin Analog on Human Melanoma Cells and Its Interaction with Standard Chemotherapeutics.

Melanoma is the leading cause of skin-cancer related deaths in North America. Metastatic melanoma is difficult to treat and chemotherapies have limited success. Furthermore, chemotherapies lead to toxic side effects due to nonselective targeting of normal cells. Curcumin is a natural product of Curcuma longa (turmeric) and has been shown to possess anti-cancer activity. However, due to its poor bioavailability and stability, natural curcumin is not an effective cancer treatment. We tested synthetic analogs of curcumin that are more stable. One of these derivatives, Compound A, has shown significant anti-cancer efficacy in colon, leukemia, and triple-negative inflammatory breast cancer cells. However, the effects of Compound A against melanoma cells have not been studied before. In this study, for the first time, we demonstrated the efficacy of Compound A for the selective induction of apoptosis in melanoma cells and its interaction with tamoxifen, taxol, and cisplatin. We found that Compound A induced apoptosis selectively in human melanoma cells by increasing oxidative stress. The anti-cancer activity of Compound A was enhanced when combined with tamoxifen and the combination treatment did not result in significant toxicity to noncancerous cells. Additionally, Compound A did not interact negatively with the anti-cancer activity of taxol and cisplatin. These results indicate that Compound A could be developed as a selective and effective melanoma treatment either alone or in combination with other non-toxic agents like tamoxifen.

Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells.

The transformation of normal cells to the cancerous stage involves multiple genetic changes or mutations leading to hyperproliferation, resistance to apoptosis, and evasion of the host immune system. However, to accomplish hyperproliferation, cancer cells undergo profound metabolic reprogramming including oxidative glycolysis and acidification of the cytoplasm, leading to hyperpolarization of the mitochondrial membrane. The majority of drug development research in the past has focused on targeting DNA replication, repair, and tubulin polymerization to induce apoptosis in cancer cells. Unfortunately, these are not cancer-selective targets. Recently, researchers have started focusing on metabolic, mitochondrial, and oxidative stress vulnerabilities of cancer cells that can be exploited as selective targets for inducing cancer cell death. Indeed, the hyperpolarization of mitochondrial membranes in cancer cells can lead to selective importing of mitocans that can induce apoptotic effects. Herein, we will discuss recent mitochondrial-selective anticancer compounds (mitocans) that have shown selective toxicity against cancer cells. Increased oxidative stress has also been shown to be very effective in selectively inducing cell death in cancer cells. This oxidative stress could lead to mitochondrial dysfunction, which in turn will produce more reactive oxygen species (ROS). This creates a vicious cycle of mitochondrial dysfunction and ROS production, irreversibly leading to cell suicide. We will also explore the possibility of combining these compounds to sensitize cancer cells to the conventional anticancer agents. Mitocans in combination with selective oxidative-stress producing agents could be very effective anticancer treatments with minimal effect on healthy cells.

Hibiscus flower extract selectively induces apoptosis in breast cancer cells and positively interacts with common chemotherapeutics.

BACKGROUND: Current therapeutic approaches to treat metastatic breast cancer, although effective, have shown many inadvertent side effects such as genotoxicity due to a lack of selectivity. Thus, these treatment plans are not suitable for long-term usage. Natural health product extracts are safe for long-term consumption and some have shown to be medicinally active containing multiple bioactive compounds able target multiple vulnerabilities in cancer. One of which, Hibiscus rosa-sinesis (hibiscus) extract, has been reported to have many medicinal and anticancer properties due to its antioxidant and hypolipidemic effects. However, its efficacy against breast cancer has not been fully investigated and characterized. If effective against cancer, hibiscus extract could potentially be combined with chemotherapeutic treatments in adjuvant therapy to reduce chemotherapy-inducing side effects. METHOD: We have investigated aqueous hibiscus flower extract anticancer efficacy, selectivity, and interactions with chemotherapeutics taxol, cisplatin, and tamoxifen in estrogen-receptor positive breast cancer cells, triple-negative human breast cancer cells, and normal non-cancerous cells. Apoptotic morphology and biochemical marker expression were assessed to determine the extent anticancer efficacy of hibiscus. Mitochondrial membrane potential reduction and reactive oxygen species generation were quantified using fluorogenic dyes to determine the mechanism of hibiscus extract action. RESULTS: Hibiscus extract was able to selectively induce apoptosis in both triple-negative and estrogen-receptor positive breast cancer cells in a dosage-dependent manner. Most importantly, addition of hibiscus extract was found to enhance the induction of apoptosis of chemotherapy treatments (taxol and cisplatin) in triple-negative breast cancer cells when compared to treatment alone. Moreover, hibiscus extract addition to chemotherapy treatment was able to increase oxidative stress and decrease mitochondrial membrane potential compared to individual treatments. CONCLUSION: Hibiscus extract is effective on breast cancer, most notably on generally resistant triple-negative breast cancer, while being selective for normal healthy cells. Hibiscus extract could supplement chemotherapeutic regimens as an adjuvant and lead to a more efficacious treatment approach to reduce chemotherapy dosages and related toxicity.

A Bird's-Eye View of the Multiple Biochemical Mechanisms that Propel Pathology of Alzheimer's Disease: Recent Advances and Mechanistic Perspectives on How to Halt the Disease Progression Targeting Multiple Pathways.

Neurons consume the highest amount of oxygen, depend on oxidative metabolism for energy, and survive for the lifetime of an individual. Therefore, neurons are vulnerable to death caused by oxidative-stress, accumulation of damaged and dysfunctional proteins and organelles. There is an exponential increase in the number of patients diagnosed with neurodegenerative diseases such as Alzheimer's (AD) as the number of elderly increases exponentially. Development of AD pathology is a complex phenomenon characterized by neuronal death, accumulation of extracellular amyloid-ß plaques and neurofibrillary tangles, and most importantly loss of memory and cognition. These pathologies are most likely caused by mechanisms including oxidative stress, mitochondrial dysfunction/stress, accumulation of misfolded proteins, and defective organelles due to impaired proteasome and autophagy mechanisms. Currently, there are no effective treatments to halt the progression of this disease. In order to treat this complex disease with multiple biochemical pathways involved, a complex treatment regimen targeting different mechanisms should be investigated. Furthermore, as AD is a progressive disease-causing morbidity over many years, any chemo-modulator for treatment must be used over long period of time. Therefore, treatments must be safe and non-interfering with other processes. Ideally, a treatment like medicinal food or a supplement that can be taken regularly without any side effect capable of reducing oxidative stress, stabilizing mitochondria, activating autophagy or proteasome, and increasing energy levels of neurons would be the best solution. This review summarizes progress in research on different mechanisms of AD development and some of the potential therapeutic development strategies targeting the aforementioned pathologies.

Resumption of Autophagy by Ubisol-Q10 in Presenilin-1 Mutated Fibroblasts and Transgenic AD Mice: Implications for Inhibition of Senescence and Neuroprotection.

Alzheimer's disease (AD) is the most prevalent form of dementia and is associated with loss of memory, amyloid-beta plaque buildup, and neurofibrillary tangles. These features might be a result of neuronal cell death in the cerebral cortex and hippocampal regions of the brain. AD pathologies can be attributed to a variety of biochemical consequences including mitochondrial dysfunction, increased oxidative stress, and autophagy inhibition. Unfortunately, current therapeutics are limited only to symptomatic relief and do not halt the progression of neurodegeneration. Previous in vitro experiments have shown that a water-soluble formulation of coenzyme-Q10, Ubisol-Q10, can stabilize the mitochondria, prevent oxidative stress, and inhibit premature senescence in fibroblasts of AD patients. Since autophagy plays a critical role in maintenance and survival of neurons, we hypothesized that Ubisol-Q10 treatment could result in resumption of autophagy. Indeed, we observed induction of autophagy by Ubisol-Q10 treatment in AD fibroblasts as well as in the brains of transgenic AD mice. We found increased expression of autophagy-related genes beclin-1 and JNK1 following Ubisol-Q10 treatment of AD fibroblasts. These results were confirmed at the protein level by immunofluorescence and Western blotting. Interestingly, despite reduction of oxidative stress in cells due to Ubisol-Q10 treatment, autophagy inhibition leads to resumption of premature senescence in these PS-1 mutated fibroblasts indicating that autophagy is critical to prevent the senescence phenotype. Withdrawal of Ubisol-Q10 treatment also leads to the return of the senescence phenotype in AD fibroblasts indicating that constant supplementation of Ubisol-Q10 is required. Additionally, Ubisol-Q10 supplementation in the drinking water of double transgenic AD mice leads to increased expression of beclin-1 and JNK1 in the cortical region. Thus, the activation of autophagy by Ubisol-Q10 could be the mechanism for its ability to halt the progression of AD pathology in transgenic AD mice shown previously.

Corrigendum: Cancer Cell Mitochondria Targeting by Pancratistatin Analogs is Dependent on Functional Complex II and III.

This corrects the article DOI: 10.1038/srep42957.

Exploiting mitochondrial and oxidative vulnerabilities with a synthetic analog of pancratistatin in combination with piperlongumine for cancer therapy.

Harsh adverse effects as a result of nonspecific targeting of chemotherapeutics currently pose obstacles in cancer therapy; thus, it would be invaluable to devise novel approaches to specifically target cancer cells. The natural compound pancratistatin (PST) has been shown to preferentially induce apoptosis in a variety of cancer cell types. Recently, several analogs of PST were shown to be efficacious in inducing apoptosis in a variety of aggressive cancer cell types via cancer cell mitochondrial targeting; it caused dissipation of mitochondrial membrane potential and decreased oxygen consumption, and with isolated mitochondria, it induced the release of apoptogenic factors. The natural compound piperlongumine has been shown to target the stress response to reactive oxygen species in cancer cells. We explored the combinatorial potential of two small molecules (SVTH-6 and piperlongumine) that target these vulnerabilities in cancer cells. Interestingly, when combined with the PST analog, SVTH-6, an increase in mitochondrial dysfunction was observed, leading to an enhanced cytotoxic effect against several human cancer cell types. Additionally, this combination treatment was effective in reducing cancer cell growth in physiologically more relevant 3-dimensional spheroid cell cultures. This enhanced effect was found to be dependent on reactive oxygen species generation because an antioxidant could rescue cancer cells from this combination treatment. Importantly, noncancerous cells were markedly less sensitive to this combination treatment. Thus, targeting mitochondrial and oxidative stress vulnerabilities of cancer cells could be an effective strategy for cancer therapy.-Ma, D., Gilbert, T., Pignanelli, C., Tarade, D., Noel, M., Mansour, F., Gupta, M., Ma, S., Ropat, J., Curran, C., Vshyvenko, S., Hudlicky, T., Pandey. S. Exploiting mitochondrial and oxidative vulnerabilities with a synthetic analog of pancratistatin in combination with piperlongumine for cancer therapy.

Ubisol-Q10 (a Nanomicellar Water-Soluble Formulation of CoQ10) Treatment Inhibits Alzheimer-Type Behavioral and Pathological Symptoms in a Double Transgenic Mouse (TgAPEswe, PSEN1dE9) Model of Alzheimer's Disease.

 Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-ß (Aß) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aß plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.

Selective Targeting of Cancer Cells by Oxidative Vulnerabilities with Novel Curcumin Analogs.

Recently, research has focused on targeting the oxidative and metabolic vulnerabilities in cancer cells. Natural compounds like curcumin that target such susceptibilities have failed further clinical advancements due to the poor stability and bioavailability as well as the need of high effective doses. We have synthesized and evaluated the anti-cancer activity of several monocarbonyl analogs of curcumin. Interestingly, two novel analogs (Compound A and I) in comparison to curcumin, have increased chemical stability and have greater anti-cancer activity in a variety of human cancer cells, including triple-negative, inflammatory breast cancer cells. In particular, the generation of reactive oxygen species was selective to cancer cells and occurred upstream of mitochondrial collapse and execution of apoptosis. Furthermore, Compound A in combination with another cancer-selective/pro-oxidant, piperlongumine, caused an enhanced anti-cancer effect. Most importantly, Compound A was well tolerated by mice and was effective in inhibiting the growth of human triple-negative breast cancer and leukemia xenografts in vivo when administered intraperitoneally. Thus, exploiting oxidative vulnerabilities in cancer cells could be a selective and efficacious means to eradicate malignant cells as demonstrated by the curcumin analogs presented in this report with high therapeutic potential.

Structurally simplified biphenyl combretastatin A4 derivatives retain in vitro anti-cancer activity dependent on mitotic arrest.

The cis-stilbene, combretastatin A4 (CA4), is a potent microtubule targeting and vascular damaging agent. Despite promising results at the pre-clinical level and extensive clinical evaluation, CA4 has yet to be approved for therapeutic use. One impediment to the development of CA4 is an inherent conformational instability about the ethylene linker, which joins two aromatic rings. We have previously published preliminary data regarding structurally simplified biphenyl derivatives of CA4, lacking an ethylene linker, which retain anti-proliferative and pro-apoptotic activity, albeit at higher doses. Our current study provides a more comprehensive evaluation regarding the anti-proliferative and pro-apoptotic properties of biphenyl CA4 derivatives in both 2D and 3D cancerous and non-cancerous cell models. Computational analysis has revealed that cytotoxicity of CA4 and biphenyl analogues correlates with predicted tubulin affinity. Additional mechanistic evaluation of the biphenyl derivatives found that their anti-cancer activity is dependent on prolonged mitotic arrest, in a similar manner to CA4. Lastly, we have shown that cancer cells deficient in the extrinsic pathway of apoptosis experience delayed cell death following treatment with CA4 or analogues. Biphenyl derivatives of CA4 represent structurally simplified analogues of CA4, which retain a similar mechanism of action. The biphenyl analogues warrant in vivo examination to evaluate their potential as vascular damaging agents.

Cancer Cell Mitochondria Targeting by Pancratistatin Analogs is Dependent on Functional Complex II and III.

Enhanced mitochondrial stability and decreased dependence on oxidative phosphorylation confer an acquired resistance to apoptosis in cancer cells, but may present opportunities for therapeutic intervention. The compound pancratistatin (PST) has been shown to selectively induce apoptosis in cancer cells. However, its low availability in nature has hindered its clinical advancement. We synthesized PST analogs and a medium-throughput screen was completed. Analogs SVTH-7, -6, and -5 demonstrated potent anti-cancer activity greater than PST and several standard chemotherapeutics. They disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced growth of tumor xenografts in vivo. Interestingly, the pro-apoptotic effects of SVTH-7 on cancer cells and mitochondria were abrogated with the inhibition of mitochondrial complex II and III, suggesting mitochondrial or metabolic vulnerabilities may be exploited by this analog. This work provides a scaffold for characterizing distinct mitochondrial and metabolic features of cancer cells and reveals several lead compounds with high therapeutic potential.