Mitochondria Of Cancer Cells Research Articles

Mitochondria in relation to cancer metastasis: introduction to a mini-review series

This introductory article and those that follow focus on the roles that mitochondria may have in cancer metastasis (spreading) that all too frequently leads to death of cancer patients. The history of cancer dates back in time to several thousand years BC and continues to this day. Although billions of dollars have been invested, numerous cancer researchers/scientists and oncologist located at universities, hospitals, cancer centers, commercial entities (companies), and government agencies have been unable to discover "magic bullets" to quickly silence most cancers. That is, agents that are effective not only in eradicating the primary tumor at its site of origin, but eradicating also distant tumors that have arisen therefrom via metastatic cells. Fortunately, in recent years some researchers have obtained evidence that the mitochondria of cancer cells are involved not only in providing in part the necessary energy (ATP) to fuel their growth, but hold the secrets to their immortality, and propensity to metastasize (spread) from their original site of origin to other body locations. This introductory article, as well as those that follow, focus on the possible roles of mitochondria in cancer metastasis as well as strategies to arrest cancer metastasis based on this knowledge. Ideally, for a patient to become "cancer free" the anticancer agent/agents used must 1) eradicate the primary tumor at its site of origin, 2) eradicate any tumors at other body locations that have arisen via metastasis, and 3) eradicate any tumor cells that remain in the blood, i.e., circulating tumor cells. One such agent that holds promise for doing all three is the small molecule 3-bromopyruvate (3BP) discovered in the author's laboratory by Dr. Young H. Ko near the turn of the century to be a potent anti-cancer agent [Ko et al.(2001) Can Lett 173:83-91].

Tipping the Balance in the Powerhouse of the Cell to “Protect” Colorectal Cancer

Tipping the Balance in the Powerhouse of the Cell to “Protect” Colorectal Cancer

Abstract 3466: Mitochondrial targeting photosensitizer-lipophilic cation conjugates for photodynamic therapy

Abstract Mitochondrion of a living cell plays a pivotal role in apoptosis. Targeting the mitochondria of cancer cell for the induction of apoptosis in photodynamic therapy (PDT) has gained importance. Cancer cells have higher plasma and mitochondrial membrane potential compared to normal cells, consequently delocalized lipophilic cations (DLCs) tend to accumulate more in them than in normal cells. In PDT photosensitizers can be specifically delivered to the mitochondria of cancerous cell by conjugating them with DLCs. Three conjugates: CMP-TPP (a porphyrin-triphenyl phosphene monocation conjugate) and CMP-(TPP)2 (a porphyrin- triphenyl phosphene dication conjugate), CMP-Rh (a porphyrin -rhodamine monocation conjugate) were synthesized as mitochondria targeting photosensitizers. The conjugates were synthesized by conjugating a core modified porphyrin (CMP-TPP) to either 1 or 2 triphenyl phosphene (TPP) molecules or rhodamine B (Rh B) respectively via a saturated hydrocarbon linker. To evaluate the efficiency of the conjugates, the photophysical properties like fluorescence resonance energy transfer (FRET in CMP-Rh) and singlet oxygen generation was compared to that of the unconjugated CMP. Potent in vitro photodynamic activity was observed in Colon 26 cells upon treatment with CMP conjugates and exposure to 690 nm diode laser light source (5.6 mW/cm2 for 30 min, 10.8 J/cm2). No significant darktotoxicity was observed in cells treated up to 5 μM of the conjugates. The conjugates showed approximately 12-14 times higher uptake in Colon 26 cells compared to unconjugated porphyrin. Further, sub-cellular localization, comparison of preferential uptake by cancerous cells versus normal cells, in vivo bio-distribution, PDT in BALB/c mice will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3466. doi:1538-7445.AM2012-3466

The effect of bile acids on mitochondrial mass and activity in normal and cancer cells

Barrett's esophagus is a condition where normal squamous epithelium is replaced by metaplastic columnar epithelium. This condition is associated with an increased risk for the development of esophageal adenocarcinoma, which is linked to the reflux of bile acids. Our study was to compare the effect of bile acids (deoxycholic acid, DCA) on cytotoxicity, mitochondrial mass and activity in esophageal adenocarcinoma cells (JHEsoAd) and non dysplastic Barret's esophagus (CP‐A). Cytotoxicity was examined by SRB colorimetric assays, the activity of mitochondrial dehydrogenases was evaluated by MTS assay and mitochondrial mass was examined by MitoTracker Green and Hoechst staining. SRB showed a decrease in protein concentration in CP‐A cells exposed to DCA compared to untreated cells. A similar decrease was observed in JHEsoAd cells exposed to DCA. MTS showed a decrease in mitochondrial activity in CP‐A cells exposed to DCA but, the opposite effect was detected in JHEsoAd cells exposed to DCA. The ratio of the number of mitochondria (MitoTracker Green) and the number of cells (Hoechst) was observed. This ratio was increased in JHEsoAd1 cells but not in CP‐A cells. This indicated that the mitochondria in cancer cells respond differently to stress induced by bile acids and are crucial for apoptosis induction. Therefore, we will further evaluate the role of mitochondria in bile‐acid induced cancer development.

Preservation of NADH ubiquinone-oxidoreductase activity by Src kinase-mediated phosphorylation of NDUFB10

The tyrosine kinase Src is upregulated in several cancer cells. In such cells, there is a metabolic reprogramming elevating aerobic glycolysis that seems partly dependent on Src activation. Src kinase was recently shown to be targeted to mitochondria where it modulates mitochondrial bioenergetics in non-proliferative tissues and cells. The main goal of our study was to determine if increased Src kinase activity could also influence mitochondrial metabolism in cancer cells (143B and DU145 cells). We have shown that 143B and DU145 cells produce most of the ATP through glycolysis but also that the inhibition of OXPHOS led to a significant decrease in proliferation which was not due to a decrease in the total ATP levels. These results indicate that a more important role for mitochondria in cancer cells could be ensuring mitochondrial functions other than ATP production. This study is the first to show a putative influence of intramitochondrial Src kinase on oxidative phosphorylation in cancer cells. Indeed, we have shown that Src kinase inhibition led to a decrease in mitochondrial respiration via a specific decrease in complex I activities (NADH–ubiquinone oxidoreductase). This decrease is associated with a lower phosphorylation of the complex I subunit NDUFB10. These results suggest that the preservation of complex I function by mitochondrial Src kinase could be important in the development of the overall phenotype of cancer.

Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism

It is well known that ErbB2, a receptor tyrosine kinase, localizes on the plasma membrane. Here we describe a novel observation that ErbB2 also localizes in mitochondria of cancer cells and patient samples. We found that ErbB2 translocates into mitochondria through the association with mtHSP70. Additionally, mitochondrial ErbB2 (mtErbB2) negatively regulates mitochondrial respiratory functions. Oxygen consumption and activities of complexes of the mitochondrial electron transport chain were decreased in mtErbB2-overexpressing cells. Mitochondrial membrane potential and the cellular ATP level also were decreased. In contrast, mtErbB2 enhanced cellular glycolysis. The translocation of ErbB2 and its impact on mitochondrial function are kinase dependent. Interestingly, cancer cells with higher levels of mtErbB2 were more resistant to ErbB2 targeting antibody trastuzumab. Our study provides a novel perspective on the metabolic regulatory function of ErbB2 and reveals that mtErbB2 plays an important role in the regulation of cellular metabolism and cancer cell resistance to therapeutics.

Power Surge: Supporting Cells “Fuel” Cancer Cell Mitochondria

An emerging paradigm in tumor metabolism is that catabolism in host cells "fuels" the anabolic growth of cancer cells via energy transfer. A study in Nature Medicine (Nieman et al., 2011) supports this; they show that triglyceride catabolism in adipocytes drives ovarian cancer metastasis by providing fatty acids as mitochondrial fuels.

Priming Cancer Cells for Death

The effects of Bcl-2 family proteins on mitochondria in cancer cells are linked to clinical responses to chemotherapy.

Abstract A128: Dual properties of fluorescence probe and anticancer agent of small molecules developed for cancer research.

Abstract The dual properties of fluorescence probe for cancer diagnosis and G-quadruplex (G4) stabilizer for cancer treatment of 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) [1,2] inspire us to develop second-generation BMVC derivatives. A number of distinct BMVC derivatives were synthesized to investigate the correlation between cellular response and biological function of BMVC derivatives for cancer treatment. The fluorescence properties of BMVC derivatives allow us to visualize the cellular localization and possibly monitor the drug-target interaction. Together with their biological and toxicological analyzes, the correlation between cellular response and biological function of BMVC derivatives may allow us to elucidate their therapeutic mechanisms for cancer treatments. Here we have evaluated the efficacy of two BMVC derivatives, 3,6-bis(1-methyl-4-vinylpyridinium iodide)-9-(1-(1-methyl-piperidinium iodide)-3,6,9-trioxaundecane) carbazole (BMVC-8C3O) and 3,6-bis(1-methyl-4-vinylpyridinium iodide)-9-(1-(1-methyl-piperidinium iodide) dodecyl) carbazole (BMVC-12C), in CL1-0 cancer treatment. Both molecules are mainly detected in lysosome of MRC-5 normal cells. However, BMVC-12C is mainly accumulated in mitochondria of cancer cells, while BMVC-8C3O is distributed in nucleus and mitochondria of cancer cells. Although BMVC-8C3O is a better G4 stabilizer than BMVC-12C to human telomeres, BMVC-12C inhibits population doubling of CL1-0 cancer cells earlier than BMVC-8C3O. Apparently, they have different therapeutic mechanisms. Fluorescence imaging showed competition of BMVC-12C with Mitotracker red into mitochondria, implying that BMVC-12C probably accumulates into mitochondria inner membrane. The accumulation of BMVC-12C in mitochondria induces cytochrome C release and cell death. In addition, CL1-0 cancer cells treated by BMVC-12C for 72 h will lose mitochondria membrane potential and increase the level of reactive oxygen species. Our results suggest that BMVC-12C is a novel mitochondriotoxic molecule.

Abstract C168: Cancer-selective mitochondrial copper transport by elesclomol results in potent single agent efficacy in multiple tumor types.

Abstract Elesclomol is a first-in-class investigational drug that exerts potent anticancer activity through the elevation of reactive oxygen species (ROS) levels and is currently under clinical evaluation as a novel anticancer therapeutic. We recently demonstrated that elesclomol preferentially binds extracellular copper (Cu) and selectively transports this metal ion to the mitochondria of tumor cells to promote mitochondrial ROS generation and subsequent apoptosis. Here we report that elesclomol-induced copper transport and apoptosis is tumor selective. Comparative analysis using human PBMCs and the promyelocytic tumor cell line HL-60 demonstrated increased Cu levels in the mitochondrial fraction of HL-60 cells following elesclomol-Cu treatment, but not in donor PBMCs. Further, elesclomol-Cu induces ROS in HL-60-derived mitochondria but not in those isolated from PBMCs. These results suggest that elesclomol-Cu selectively targets cancer cell mitochondria to ultimately produce critical elevations in oxidative stress. To evaluate increased exposure to elesclomol-Cu in vivo, elesclomol was administered continuously to tumor-bearing mice using an Alzet pump at a clinically relevant dose. Upon release, elesclomol immediately chelates copper from the blood to form an elesclomol-Cu complex, achieving 10-fold higher levels of elesclomol-Cu compared to those following bolus injection. Even with this increased formation of elesclomol-Cu in situ, no signs of toxicity have been observed. In five different tumor xenograft models tested, elesclomol consistently demonstrated marked single agent activity with significant tumor growth suppression, indicating that increased elesclomol-Cu levels result in selective and enhanced antitumor efficacy. These findings highlight a unique mechanism of action of elesclomol and support potential single agent activity of this compound in a variety of tumor types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C168.

Mitochondrial Peroxiredoxin III is a Potential Target for Cancer Therapy

Mitochondria are involved either directly or indirectly in oncogenesis and the alteration of metabolism in cancer cells. Cancer cells contain large numbers of abnormal mitochondria and produce large amounts of reactive oxygen species (ROS). Oxidative stress is caused by an imbalance between the production of ROS and the antioxidant capacity of the cell. Several cancer therapies, such as chemotherapeutic drugs and radiation, disrupt mitochondrial homeostasis and release cytochrome c, leading to apoptosome formation, which activates the intrinsic pathway. This is modulated by the extent of mitochondrial oxidative stress. The peroxiredoxin (Prx) system is a cellular defense system against oxidative stress, and mitochondria in cancer cells are known to contain high levels of Prx III. Here, we review accumulating evidence suggesting that mitochondrial oxidative stress is involved in cancer, and discuss the role of the mitochondrial Prx III antioxidant system as a potential target for cancer therapy. We hope that this review will provide the basis for new strategic approaches in the development of effective cancer treatments.

Abstract B56: Organelle targeted photodynamic therapy

Abstract The success of a cancer treatment is directly related to its ability to selectively kill cancer cells. Photodynamic therapy (PDT) with a photosensitizer (PS) that targets mitochondria causes a prompt release of cytochrome c into the cytoplasm and activation of caspases-9 and -3, among other caspases, that are responsible for initiating cell degradation. Photofrin is the FDA approved drug for PDT. Mitochondria have repeatedly been implicated as primary targets of porphyrin mediated PDT. However, a systematic study to direct the PDT drugs towards their cellular target, mitochondria of the cancer cell, is not yet fully explored. Phthalocyanins (Pc) are a class of compounds, which are known to successfully address the drawbacks exhibited by the porphyrin-based compounds. PDT, using the second-generation Pc, causes mitochondrial damage and induces apoptosis. However, the Pc molecules are hydrophobic and must be encapsulated within a liposomal formulation for successful delivery. Given that most effective PDT drug candidates act on the mitochondria of cancer cells and their hydrophobicity require suitable delivery vehicles for their intracellular accumulation, we hypothesize that the construction of engineered targeted drug delivery systems to direct PDT drugs to the mitochondria of the cancer cells would allow an effective phototherapeutic action. This would result in a higher local concentration of singlet oxygen in the mitochondria of cancer cells. In order to study this hypothesis, we have initiated the synthesis of a series of mitochondria targeting polymers to study nanoparticle (NP) assisted targeted delivery and anticancer properties of metallo phthalocyanins. The synthesis and biological activity of these constructs will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B56.

Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells

The small, water soluble molecule Dichloroacetate (DCA) is recently arousing lively interests in the field of cancer therapy for it has been shown to be able to inhibit the growth of human tumors acting specifically on the mitochondria of cancer cells without perturbing the physiology of nonmalignant cells. Neuroblastoma was one of the tumor types on which DCA was considered ineffective as it is composed of cells with few recognized mitochondrial anomalies. Neuroblastoma, however, is composed of different cell types in terms of metabolism, phenotype and malignant potential. Despite the above prediction, in this work, we show that (i) DCA exhibits an unexpected anticancer effect on NB tumor cells and (ii) this effect is selectively directed to very malignant NB cells, whereas the more differentiated/less malignant NB cells are refractory to DCA treatment. This result supports the need of a detailed investigation of DCA anticancer properties against this tumor type with the final aim of its possible use as therapeutic agent.

Understanding the metabolic basis of drug resistance

Previously, we identified a form of epithelial-stromal metabolic coupling, in which cancer cells induce aerobic glycolysis in adjacent stromal fibroblasts, via oxidative stress, driving autophagy and mitophagy. In turn, these cancer-associated fibroblasts provide recycled nutrients to epithelial cancer cells, "fueling" oxidative mitochondrial metabolism and anabolic growth. An additional consequence is that these glycolytic fibroblasts protect cancer cells against apoptosis, by providing a steady nutrient stream of to mitochondria in cancer cells. Here, we investigated whether these interactions might be the basis of tamoxifen-resistance in ER(+) breast cancer cells. We show that MCF7 cells alone are Tamoxifen-sensitive, but become resistant when co-cultured with hTERT-immortalized human fibroblasts. Next, we searched for a drug combination (Tamoxifen + Dasatinib) that could over-come fibroblast-induced Tamoxifen-resistance. Importantly, we show that this drug combination acutely induces the Warburg effect (aerobic glycolysis) in MCF7 cancer cells, abruptly cutting off their ability to use their fuel supply, effectively killing these cancer cells. Thus, we believe that the Warburg effect in tumor cells is not the "root cause" of cancer, but rather it may provide the necessary clues to preventing chemo-resistance in cancer cells. Finally, we observed that this drug combination (Tamoxifen + Dasatinib) also had a generalized anti-oxidant effect, on both co-cultured fibroblasts and cancer cells alike, potentially reducing tumor-stroma co-evolution. Our results are consistent with the idea that chemo-resistance may be both a metabolic and stromal phenomenon that can be overcome by targeting mitochondrial function in epithelial cancer cells. Thus, simultaneously targeting both (1) the tumor stroma and (2) the epithelial cancer cells, with combination therapies, may be the most successful approach to anti-cancer therapy. This general strategy of combination therapy for overcoming drug resistance could be applicable to many different types of cancer.

Abstract 578: Roles of mitochondrial protein kinases in targeted cancer therapy

Abstract Targeted cancer therapy is based on the curious dependence that some cancer cells have on a single oncogenic molecule, typically a protein kinase (the phenomenon of “oncogene addiction”). However, the molecular mechanisms of such dependence are incompletely understood. We have adopted a quantitative proteomic approach to investigate the phenomenon that MET-overexpressing cancer cells are paradoxically more sensitive to MET inhibition than cells with basal MET expression. Unexpectedly, we found that mitochondria are a direct target of MET kinase inhibition, in addition to inhibition of plasma membrane MET. Effects on activated MET in the mitochondria of cancer cells that are sensitive to MET inhibition could reflect a novel and critical non-canonical mechanism that contributes to the efficacy of MET-targeted therapeutics. We hypothesize that protein kinases which aberrantly translocate to mitochondria modulate mitochondrial proteins and functions. Here we have employed advanced LC-MS/MS-based stable isotope labeling with amino acids in cell culture (SILAC) quantitative phosphoproteomic approaches to identify, quantify and functionally annotate phosphorylated mitochondrial proteins of various cancer cell lines, including those that are sensitive or resistant to targeted agents. We identified several phosphorylated protein kinases e.g. MET, EGFR, HER2 and HER3, that were translocated to mitochondria of cancer cells. In addition to documenting the first kinome and phosphoproteome of mitochondria in cancer cells, we present evidence showing that the aberrant presence of protein kinases in mitochondria predicts sensitivity to specific kinase inhibitors. In conclusion, our data reveal a novel mitochondrial mechanism of oncogene addiction, and suggest that mitochondrial protein kinases might play decisive roles in molecularly-directed therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 578. doi:10.1158/1538-7445.AM2011-578

The selective growth inhibition of oral cancer by iron core-gold shell nanoparticles through mitochondria-mediated autophagy

Nanoparticles with an iron core and gold shell (denoted “Fe@AuÓ”) have been reported to limit cancer-cell proliferation and therefore have been proposed as a potential anti-cancer agent. However, the underlying mechanisms are still unknown. In this study, we used flow cytometry, confocal fluorescence microscopy, and transmission electron microscopy to analyse the morphological and functional alterations of mitochondria in cancerous cells and healthy cells when treated with Fe@Au. It was found that Fe@Au caused an irreversible membrane-potential loss in the mitochondria of cancer cells, but only a transitory decrease in membrane potential in healthy control cells. Production of reactive oxygen species (ROS) was observed; however, additions of common ROS scavengers were unable to protect cancerous cells from the Fe@Au-induced cytotoxicity. Furthermore, iron elements, before oxidation, triggered mitochondria-mediated autophagy was shown to be the key factor responsible for the differential cytotoxicity observed between cancerous and healthy cells.

EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: A potential mechanism of EGFR-driven antagonism of apoptosis

BackgroundEpidermal growth factor receptor (EGFR) plays an essential role in normal development, tumorigenesis and malignant biology of human cancers, and is known to undergo intracellular trafficking to subcellular organelles. Although several studies have shown that EGFR translocates into the mitochondria in cancer cells, it remains unclear whether mitochondrially localized EGFR has an impact on the cells and whether EGFRvIII, a constitutively activated variant of EGFR, undergoes mitochondrial transport similar to EGFR.ResultsWe report that both receptors translocate into the mitochondria of human glioblastoma and breast cancer cells, following treatments with the apoptosis inducers, staurosporine and anisomycin, and with an EGFR kinase inhibitor. Using mutant EGFR/EGFRvIII receptors engineered to undergo enriched intracellular trafficking into the mitochondria, we showed that glioblastoma cells expressing the mitochondrially enriched EGFRvIII were more resistant to staurosporine- and anisomycin-induced growth suppression and apoptosis and were highly resistant to EGFR kinase inhibitor-mediated growth inhibition.ConclusionsThese findings indicate that apoptosis inducers and EGFR-targeted inhibitors enhance mitochondrial translocalization of both EGFR and EGFRvIII and that mitochondrial accumulation of these receptors contributes to tumor drug resistance. The findings also provide evidence for a potential link between the mitochondrial EGFR pathway and apoptosis.

Selective Targeting of Gold Nanorods at the Mitochondria of Cancer Cells: Implications for Cancer Therapy

We have observed that Au nanorods (NRs) have distinct effects on cell viability via killing cancer cells while posing negligible impact on normal cells and mesenchymal stem cells. Obvious differences in cellular uptake, intracellular trafficking, and susceptibility of lysosome to Au NRs by different types of cells resulted in selective accumulation of Au NRs in the mitochondria of cancer cells. Their long-term retention decreased mitochondrial membrane potential and increased reactive oxygen species level that enhances the likelihood of cell death. These findings thus provide guidance for the design of organelle-targeted nanomaterials in tumor therapy.

Quantitative Proteomics Discloses MET Expression in Mitochondria as a Direct Target of MET Kinase Inhibitor in Cancer Cells

Cancer cells with MET overexpression are paradoxically more sensitive to MET inhibition than cells with baseline MET expression. The underlying molecular mechanisms are incompletely understood. Here, we have traced early responses of SNU5, a MET-overexpressing gastric cancer cell line, exposed to sublethal concentration of PHA-665752, a selective MET inhibitor, using iTRAQ-based quantitative proteomics. More than 1900 proteins were quantified, of which >800 proteins were quantified with at least five peptides. Proteins whose expression was perturbed by PHA-665752 included oxidoreductases, transfer/carrier proteins, and signaling proteins. Strikingly, 38% of proteins whose expression was confidently assessed to be perturbed by MET inhibition were mitochondrial proteins. Upon MET inhibition by a sublethal concentration of PHA-665752, mitochondrial membrane potential increased and mitochondrial permeability transition pore was inhibited concomitant with widespread changes in mitochondrial protein expression. We also showed the presence of highly activated MET in mitochondria, and striking suppression of MET activation by 50 nm PHA-665752. Taken together, our data indicate that mitochondria are a direct target of MET kinase inhibition, in addition to plasma membrane MET. Effects on activated MET in the mitochondria of cancer cells that are sensitive to MET inhibition might constitute a novel and critical noncanonical mechanism for the efficacy of MET-targeted therapeutics.

New Prospects for Nelfinavir in Non-HIV-Related Diseases

Nelfinavir (Viracept®) was originally designed as a specific HIV protease inhibitor and, since its introduction in 1997, has served as an effective, reliable, and well-tolerated HIV drug. Although nelfinavir is being increasingly displaced by second generation HIV protease inhibitors that allow better combination treatments, it has again become a focus of interest due to an interesting paradoxical effect: nelfinavir inhibits experimentally-induced tissue degeneration or cell damage by preventing loss of the mitochondrial membrane potential, and even protects mitochondria in cancer cells but, conversely, it selectively induces a mitochondria-independent cell death mechanism in cancer cells by the so-called endoplasmic reticulum/unfolded protein stress response, allowing nelfinavir to act on otherwise chemo-resistant cancer cells. Furthermore, anti-microbial effects of nelfinavir have been described, including an efficacy against malaria, tuberculosis, and SARS, mostly by cross-reacting with microbial aspartic proteases. Several cancer-related clinical studies on nelfinavir as a single agent or in combination therapies have been launched and are expected to add to the usefulness of this versatile drug for cancer treatment strategies or other purposes.