Mitochondrial-Targeting Nitrooxy-doxorubicin: A New Approach To Overcome Drug Resistance

Riganti, Chiara; Rolando, Barbara; Kopecka, Joanna; Campia, Ivana; Chegaev, Konstantin; Lazzarato, Loretta; Federico, Antonella; Fruttero, Roberta; Ghigo, Dario

doi:10.1021/mp300311b

Cited by 65 publications

(93 citation statements)

References 48 publications

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“…The chemoresistant counterpart (HT29-dx cells) line was generated by culturing parental cells in the presence of increasing concentrations of doxorubicin for 20 passages [41]. HT29-dx cells have higher Pgp, MRP1 and BCRP than HT29 cells [68]; moreover, compared to HT29 cells, HT29-dx cells have a higher IC50 for doxorubicin (25.51 ± 1.33 μM versus 2.74 ± 0.67 μM; p < 0.01), irinotecan (0.91 ± 0.18 μM versus 0.05 ± 0.01 μM; p < 0.001), oxaliplatin (98.75 ± 6.08 μM versus 4.75 ± 0.71 μM; p < 0.001), and 5-fluorouracil (8.35 ± 0.64 μM versus 1.06 ± 0.14 μM; p < 0.05), representing a reliable model of MDR cells. For the present work, HT29-dx cells were grown in medium containing 200 nM doxorubicin.…”

Section: Methodsmentioning

confidence: 99%

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

et al. 2013

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BackgroundThe activity of P-glycoprotein (Pgp) and multidrug resistance related protein 1 (MRP1), two membrane transporters involved in multidrug resistance of colon cancer, is increased by high amounts of cholesterol in plasma membrane and detergent resistant membranes (DRMs). It has never been investigated whether omega 3 polyunsatured fatty acids (PUFAs), which modulate cholesterol homeostasis in dyslipidemic syndromes and have chemopreventive effects in colon cancer, may affect the response to chemotherapy in multidrug resistant (MDR) tumors.MethodsWe studied the effect of omega 3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in human chemosensitive colon cancer HT29 cells and in their MDR counterpart, HT29-dx cells.ResultsMDR cells, which overexpressed Pgp and MRP1, had a dysregulated cholesterol metabolism, due to the lower expression of ubiquitin E3 ligase Trc8: this produced lower ubiquitination rate of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR), higher cholesterol synthesis, higher cholesterol content in MDR cells. We found that DHA and EPA re-activated Trc8 E3 ligase in MDR cells, restored the ubiquitination rate of HMGCoAR to levels comparable with chemosensitive cells, reduced the cholesterol synthesis and incorporation in DRMs. Omega 3 PUFAs were incorporated in whole lipids as well as in DRMs of MDR cells, and altered the lipid composition of these compartments. They reduced the amount of Pgp and MRP1 contained in DRMs, decreased the transporters activity, restored the antitumor effects of different chemotherapeutic drugs, restored a proper tumor-immune system recognition in response to chemotherapy in MDR cells.ConclusionsOur work describes a new biochemical effect of omega 3 PUFAs, which can be useful to overcome chemoresistance in MDR colon cancer cells.

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Section: Methodsmentioning

confidence: 99%

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

et al. 2013

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“…These were used at 20 µM in 0.25 mL of caspase assay buffer (25 mmol/L Hepes, 0.1% w/v CHAPS, 10% w/v sucrose, 10 mmol/L DTT, 0.01% w/v egg albumin, pH 7.5). The reaction was stopped by adding 0.1% w/v ice-cold trichloroacetic acid (0.75 mL) and the fluorescence of AMC fragment released by active caspases was then read (Fluoroskan Ascent fluorimeter, ThermoLabsystems, Helsinki, Finland) at 380 nm and 460 nm (excitation and emission wavelengths, respectively) [66].…”

Section: Caspase Activitymentioning

confidence: 99%

Apoptotic-Induced Effects of Acacia Catechu Willd. Extract in Human Colon Cancer Cells

Chiaino

Micucci

Budriesi

et al. 2020

IJMS

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The research for innovative treatments against colon adenocarcinomas is still a great challenge. Acacia catechu Willd. heartwood extract (AC) has health-promoting qualities, especially at the gastrointestinal level. This study characterized AC for its catechins content and investigated the apoptosis-enhancing effect in human colorectal adenocarcinoma HT-29 cells, along with its ability to spare healthy tissue. MTT assay was used to describe the time course, concentration dependence and reversibility of AC-mediated cytotoxicity. Cell cycle analysis and AV-PI and DAPI-staining were performed to evaluate apoptosis, together with ROS formation, mitochondrial membrane potential (MMP) changes and caspase activities. Rat ileum and colon rings were tested for their viability and functionality to explore AC effects on healthy tissue. Quantitative analysis highlighted that AC was rich in (±)-catechin (31.5 ± 0.82 mg/g) and (−)-epicatechin (12.5 ± 0.42 mg/g). AC irreversibly decreased cell viability in a concentration-dependent, but not time-dependent fashion. Cytotoxicity was accompanied by increases in apoptotic cells and ROS, a reduction in MMP and increases in caspase-9 and 3 activities. AC did not affect rat ileum and colon rings' viability and functionality, suggesting a safe profile toward healthy tissue. The present findings outline the potential of AC for colon cancer treatment.3 of 17 at approximately the same content level was observed (Figure 1b). The latter was assumed as a marker of the epimerization as the consequence of the process applied in decoction preparation (thermal treatment). Analysis of decoction preparations stored during very long-term period (at least two years) at room temperature in the dark, did not show loss of (−)-EC and (+)-C, nor epimerization progression, thus suggesting very high chemical stability of the preparation. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 17 period (at least two years) at room temperature in the dark, did not show loss of (−)-EC and (+)-C, nor epimerization progression, thus suggesting very high chemical stability of the preparation.

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“…{Fulda, 2010 #29}(ref) While the therapeutic potential of harnessing the mitochondrial disruptive effects of Dox has been contemplated for over a decade (18), only recently have specific molecular targeting strategies been employed to deliver Dox to mitochondria. Such strategies include liposome encapsulation (19), chemical conjugation of mitochondrial targeting moieties (20,21) chemical modification (22), and nanoparticle encapsulation (23), all of which have demonstrated the capacity to induce cell death in cancer cells, validating this therapeutic strategy. Particularly promising is the ability of these targeted compounds to overcome clinically relevant resistance mechanisms that exist outside of mitochondria.…”

Section: Introductionmentioning

confidence: 99%

“…Particularly promising is the ability of these targeted compounds to overcome clinically relevant resistance mechanisms that exist outside of mitochondria. (20)(21)(22) Previous work has demonstrated that mitochondria-targeted Dox (mtDox, see Figure 1A for structure) is able to inhibit TopoII activity in vitro, leading to the induction of apoptotic cell death in cancer cells, while evading resistance mechanisms such as the upregulation of Pgp efflux pumps in the cellular membrane. (20) This phenomenon has been observed for a number of targeted anticancer agents and is likely the result of direct mitochondrial sequestration.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity

Jean¹,

Tulumello²,

Riganti

et al. 2015

ACS Chem. Biol.

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Abstract:The highly effective anticancer agent doxorubicin (Dox), is a frontline drug used to treat a number of cancers including leukemias, ovarian, prostate, breast, and lung cancer. While Dox has a high level of activity against cancer cells, treatment is often complicated by doselimiting cardiotoxicity. For many years, this debilitating side effect is thought to originate from the drug's direct activity in the mitochondria of cardiac cells, while recent studies have shown that these are primarily downstream effect from nuclear damage. Our lab has developed a mitochondrially-targeted derivative of Dox that enables the selective study of toxicity generated by the presence of Dox in the mitochondria of H9c2 rat cardiomyocytes. We demonstrate that mitochondria-targeted doxorubicin (mtDox) lacks any direct nuclear effects, which allows the cardiomyocytes to undergo mitochondrial biogenesis. This recovery response compensates for the mitotoxic effects of Dox and prevents cell death in cardiomyocytes. In accordance with these findings, cardiac toxicity was only observed in Dox but not mtDox treated mice. This study provides valuable insight into the development of methods to effectively limit the debilitating cardiotoxic effects of Dox, and potentially of other chemotherapeutics that exert effects on multiple subcellular organelles..

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Mitochondrial-Targeting Nitrooxy-doxorubicin: A New Approach To Overcome Drug Resistance

Cited by 65 publications

References 48 publications

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

Apoptotic-Induced Effects of Acacia Catechu Willd. Extract in Human Colon Cancer Cells

Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity

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