<i>In Vitro</i> and <i>In Vivo</i> Antitumor Activity of a Novel Alkylating Agent, Melphalan-Flufenamide, against Multiple Myeloma Cells

Chauhan, Dharminder; Ray, Arghya; Viktorsson, Kristina; Spira, Jack; Paba‐Prada, Claudia; Munshi, Nikhil C.; Richardson, Paul G.; Lewensohn, Rolf; Anderson, Kenneth C.

doi:10.1158/1078-0432.ccr-12-3752

Cited by 89 publications

(139 citation statements)

References 46 publications

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…Recently a renewed scientific interest on melphalan is emerging, and major efforts have been devoted to delineate the mechanisms underlying primary or acquired melphalan-resistance (13). These efforts have already led to the design of novel regimens to overcome melphalan-resistance or to improve its anti-tumor activity (14). …”

Section: Introductionmentioning

confidence: 99%

A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

Gullà

Martino

Cantafio

et al. 2016

Clinical Cancer Research

Self Cite

106

View full text Add to dashboard Cite

Purpose The onset of drug-resistance is a major cause of treatment failure in multiple myeloma (MM). While increasing evidence is defining the role of microRNAs in mediating drug-resistance, their potential activity as drug-sensitizing agents has not yet been investigated in MM. Experimental Design Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory MM cells to melphalan. Results MiR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice. Conclusions Taken together, our findings provide the proof of concept that LNA-i-miR-221 can reverse melphalan-resistance in preclinical models of MM, providing the framework for clinical trials to overcome drug resistance and improve patient outcome in MM.

show abstract

Section: Introductionmentioning

confidence: 99%

A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

Gullà

Martino

Cantafio

et al. 2016

Clinical Cancer Research

Self Cite

106

View full text Add to dashboard Cite

show abstract

“…It has demonstrated high preclinical activity even in melphalan resistant cells, based on a preferential delivery of melphalan to tumor cells due to the intracellular cleavage of melflufen by some peptidases overexpressed in malignant cells. [133]…”

Section: Clinical Results With the Most Promising Novel Agents Under mentioning

confidence: 99%

Future agents and treatment directions in multiple myeloma

Ocio

Mitsiades

Orłowski

et al. 2013

Expert Review of Hematology

View full text Add to dashboard Cite

Summary The development of bortezomib and IMIDs resulted in a revolution in the treatment of MM. Moreover, second-generation proteasome inhibitors (carfilzomib) and IMIDs (pomalidomide) have recently been approved. Nevertheless, the incurability of this disease requires other drugs with different mechanisms of action to either prolong the survival of patients refractory to current therapies, or achieve cure. Active research has been done exploring the pathogenesis of MM and searching for novel druggable targets. In this regard, some of these novel agents seem promising, such as monoclonal antibodies (anti-CD38 - daratumumab or anti-CS1 - elotuzumab) or the kinesin protein inhibitor Arry-520. Other agents under investigation are kinase inhibitors, signaling pathways inhibitors or deacetylase inhibitors. With so many novel agents under investigation, future therapy in MM will probably involve the combined use of the already approved drugs with some of those newly discovered.

show abstract

“…Each group was tested in 4 replicates. Cell concentrations were calculated by equation 1 at 525 nm [23,24,25,26,27]. …”

Section: Methodsmentioning

confidence: 99%

Design of Finasteride-Loaded Nanoparticles for Potential Treatment of Alopecia

Roque

Dias²,

Cruz³

et al. 2017

Skin Pharmacol Physiol

View full text Add to dashboard Cite

Background/Aims: Androgenetic alopecia is an extremely common dermatological disorder affecting both men and women. Oral finasteride (FNS), a synthetic 4-aza-3-oxosteroid compound with poor aqueous solubility, blocks the peripheral conversion of testosterone to dihydrotestosterone (DHT) in a significant reduction in DHT concentration, achieving satisfactory results in alopecia treatment. However, its oral intake generally causes severe side effects. Considering that there is currently no scientifically proven treatment, new drug delivery systems able to improve alopecia therapy are urgently required. Methods: In this study, polymeric nanoparticles have been proposed as a new carrier for topical delivery of FNS in hair follicles. Results and Conclusions: Polymeric nanoparticles, prepared by using a modified method of the emulsification/solvent diffusion, showed a mean particle size around 300 nm, which may be sufficient for reaching the dermis and hair follicles and negative zeta potential values. Scanning electron microscope measurements showed that all the polymeric nanoparticles exhibited a spherical shape and a smooth surface regardless of their composition. A high encapsulation efficiency was achieved for FNS (79.49 ± 0.47%). In vitro release assays in physiological conditions demonstrated that nanoparticles yielded a prolonged release of FNS for 3 h. Skin assays through an in vitro permeation study demonstrated that nanoparticles had low levels of penetration of FNS, improving its time residence onto the skin. All excipients used in nanoparticle composition and in 3 different vehicles were safe. These results suggest that the proposed novel formulation presents several good characteristics indicating its suitability for dermal delivery of FNS for alopecia treatment.

show abstract

In Vitro and In Vivo Antitumor Activity of a Novel Alkylating Agent, Melphalan-Flufenamide, against Multiple Myeloma Cells

Cited by 89 publications

References 46 publications

A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

Future agents and treatment directions in multiple myeloma

Design of Finasteride-Loaded Nanoparticles for Potential Treatment of Alopecia

Contact Info

Product

Resources

About