Salinomycin derivatives exhibit activity against primary acute lymphoblastic leukemia (ALL) cells in vitro

Urbaniak, Alicja; Delgado, Magdalena; Antoszczak, Michał; Huczyński, Adam; Chambers, Timothy C.

doi:10.1016/j.biopha.2018.01.081

Cited by 23 publications

(26 citation statements)

References 43 publications

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“…These modifications provide new SAL molecules with improved stability and unaffected selective properties against CSCs, particularly effective in overcoming chemoresistant forms of the disease [28,29]. However, the synthesis of selective SAL derivatives is complicated due to the presence of multiple functional groups and a sensitive tricyclic 6-6-5 bis-spiroketal ring system in SAL structure [20,29,30].…”

Section: Discussionmentioning

confidence: 99%

“…It was clearly proven that chemical modification of SAL and other polyether ionophores may not only increase the biological activity of resulting derivatives but also reduce their general toxicity [18][19][20][21]. Furthermore, SAL with a modified C1 carboxyl group (amides or esters) transports cations by a biomimetic mechanism, while chemically unmodified SAL transports cations through biological membranes via an electroneutral mechanism [22,23].…”

Section: In Vitro Activity Of Cytotoxic Drugs Salinomycin and Its Dmentioning

confidence: 99%

“…We devised a library of SAL derivatives based on the most active SAL amides and esters obtained in our previous studies by a chemical modification of C1 carboxyl group, i.e., amides 2 and 3, as well as esters 5 and 6, respectively (Figure 1) [18][19][20]. To expand structural diversity at C1 position and to better determine the structure-activity relationship (SAR), we additionally analyzed propargyl amide 4 and propargyl ester 7 (Figure 1), as these structures had shown promising bioactivity [19].…”

Section: In Vitro Activity Of Cytotoxic Drugs Salinomycin and Its Dmentioning

confidence: 99%

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Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

et al. 2020

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Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC50 values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs—5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Section: In Vitro Activity Of Cytotoxic Drugs Salinomycin and Its Dmentioning

confidence: 99%

Section: In Vitro Activity Of Cytotoxic Drugs Salinomycin and Its Dmentioning

confidence: 99%

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Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

et al. 2020

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“…Because SAL exhibits so many diverse biological activities, there is significant interest in developing bioactive derivatives, especially since several SAL analogues examined to date exhibit superior biological activity than the parent structure . For example, our previous studies have indicated that derivatization of the C1 carboxylate moiety of SAL with amide, ester, or bioconjugate modifications generates compounds with higher potency and selectivity compared to commonly used chemotherapeutics, such as cisplatin or doxorubicin . Similarly, chemical modification of SAL at the C20 hydroxy group generates analogues superior to the starting compound …”

Section: Introductionmentioning

confidence: 99%

“…[22] For example, our previous studies have indicated that derivatization of the C1 carboxylate moiety of SAL with amide, ester, or bioconjugate modifications generates compounds with higher potency and selectivity compared to commonly used chemotherapeutics, such as cisplatin or doxorubicin. [23][24][25][26][27][28][29] Similarly, chemical modification of SAL at the C20 hydroxy group generates analogues superior to the starting compound. [30][31][32][33][34][35][36][37][38][39] We have recently exploited these findings to synthesize doubly modified SAL derivatives at the C1 and C20 positions that are highly promising anticancer agents both in vitro and ex vivo.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticancer Activity of Tertiary Amides of Salinomycin and Their C20‐oxo Analogues

et al. 2019

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The polyether ionophore salinomycin (SAL) has captured much interest because of its potent activity against cancer cells and cancer stem cells. Our previous studies have indicated that C1/C20 double‐modification of SAL is a useful strategy to generate diverse agents with promising biological activity profiles. Thus, herein we describe the synthesis of a new class of SAL analogues that combine key modifications at the C1 and C20 positions. The activity of the obtained SAL derivatives was evaluated using primary acute lymphoblastic leukemia, human breast adenocarcinoma and normal mammary epithelial cells. One single‐ [N,N‐dipropyl amide of salinomycin (5 a)] and two novel double‐modified analogues [N,N‐dipropyl amide of C20‐oxosalinomycin (5 b) and piperazine amide of C20‐oxosalinomycin (13 b)] were found to be more potent toward the MDA‐MB‐231 cell line than SAL or its C20‐oxo analogue 2. When select analogues were tested against the NCI‐60 human tumor cell line panel, 4 a [N,N‐diethyl amide of salinomycin] showed particular activity toward the ovarian cancer cell line SK‐OV‐3. Additionally, both SAL and 2 were found to be potent ex vivo against human ER/PR+, Her2− invasive mammary carcinoma, with 2 showing minimal toxicity toward normal epithelial cells. The present findings highlight the therapeutic potential of SAL derivatives for select targeting of different cancer types.

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Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells—in vitro and ex vivo study

Urbaniak

Jousheghany

Piña‐Oviedo

et al. 2020

J Biochem & Molecular Tox

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Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N‐carbamates of N‐deacetyl‐4‐(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti‐proliferative activity than COL (IC50 = 8.6 nM) towards primary ALL cells in cell viability assays (IC50 range of 1.1‐6.4 nM), and several were more potent towards primary IDCG3 (IC50 range of 0.1 to 10.3 nM) or MC (IC50 range of 2.3‐9.1 nM) compared to COL (IC50 of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non–small‐cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer.

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Salinomycin derivatives exhibit activity against primary acute lymphoblastic leukemia (ALL) cells in vitro

Cited by 23 publications

References 43 publications

Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives—An In Vitro Study

Synthesis and Anticancer Activity of Tertiary Amides of Salinomycin and Their C20‐oxo Analogues

Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells—in vitro and ex vivo study

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