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

Ma, Dennis; Gilbert, Tyler; Pignanelli, Christopher; Tarade, Daniel; Noel, Megan; Mansour, Fadi; Gupta, Manika; Ma, Sabrina; Ropat, Jesse; Curran, Colin; Vshyvenko, Sergey; Hudlický, Tomáš; Pandey, Siyaram

doi:10.1096/fj.201700275r

Cited by 11 publications

(9 citation statements)

References 34 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, literature reports also indicated the possibility of combining PL with other substances of natural origins. The available data indicate that treatments with pancratystatin (PST) and PL cause areduction in the survival of pancreatic cancer cells [55]. Similar combinations with cytostatics have been studied in the case of the second alkaloid used-SAN.…”

Section: Discussionmentioning

confidence: 99%

The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer

et al. 2020

View full text Add to dashboard Cite

Background: Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids—piperlongumine (PL), sanguinarine (SAN) and their combination—on the basic life processes of the A549 cell line was considered reasonable. Methods: The aim was achieved by analyzing the cytotoxic effects of PL and SAN and their combination in the ratio of 4:1 on the induction of cell death, changes in the distribution of cell cycle phases, reorganization of cytoskeleton and metastatic potential of A549 cells. The versatility of the applied concentration ratio was evaluated in terms of other cancer cell lines: MCF-7, H1299 and HepG2. Results: The results obtained from the MTT assay indicated that the interaction between the alkaloids depends on the concentration and type of cells. Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells. The combined effects of PL and SAN increased apoptosis and favored metastasis inhibition. Conclusion: Selected alkaloids exhibit a cytotoxic effect on A549 cells. In turn, treatment with the combination of PL and SAN in a 4:1 ratio indicates a synergistic effect and is associated with an increase in the level of reactive oxygen species (ROS).

show abstract

Section: Discussionmentioning

confidence: 99%

The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Tamoxifen is a well-tolerated ER antagonist used for ER positive breast cancer patients and has also been shown to target the mitochondria and induce autophagy [36]. A synergistic induction of apoptosis and autophagy was observed when tamoxifen was combined with an analog of pancratistatin, another mitochondria targeting compound [14]. Likewise, when tamoxifen was combined with curcumin, a synergistic induction of apoptosis and autophagy was observed [29].…”

Section: Discussionmentioning

confidence: 99%

“…Induction of cancer cell death selectively can occur through targeting the unique characteristics of cancerous cells. For example, analogs of the natural compound pancratistatin (PST) were able to induce apoptosis selectively in cancer cells through disrupting the mitochondrial membrane potential and the release of apoptogenic factors [14,15]. Cancer cells also display higher basal levels of reactive oxygen species (ROS), which promotes tumor proliferation and progression [16,17].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, external sources of ROS or agents that stimulate oxidative stress may target cancer cells selectively [16]. For example, the natural compound piperlongumine induces cell death selectively through targeting the oxidative pathway [14]. An enhanced cytotoxic effect was observed when piperlongumine was combined with a pancratistatin analog, an activator of the intrinsic pathway of apoptosis through mitochondrial targeting [15].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Our studies on PST analog SVTH-7 indicated that combination treatment with oxidative stress inducing piperlongumine (PL) led to a more efficacious treatment that dissipated the MMP, decreased oxygen consumption, and induced the release of many apoptogenic factors from the mitochondria [155]. Because of the hyperpolarization of the mitochondria in cancer cells, the PST analogs were able to selectively target cancer, possibly through the processing and uptake of PST analogs in positively charged molecules to be brought to only cancer cell mitochondria.…”

Section: Strategies To Target Mitochondriamentioning

confidence: 99%

Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells

Nguyen

Pandey

2019

Cancers

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 11 publications

References 34 publications

The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer

The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer

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

Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells

Contact Info

Product

Resources

About