Metallothionein-3 promotes cisplatin chemoresistance remodelling in neuroblastoma

Rodrigo, Miguel Ángel Merlos; Michalkova, Hana; Strmiska, Vladislav; Casar, Berta; Crespo, Piero; Rı́os, Vivian de los; Casal, J. Ignacio; Haddad, Yazan; Guráň, Roman; Eckschlager, Tomáš; Pokorná, Petra; Heger, Zbyněk; Adam, Vojtěch

doi:10.1038/s41598-021-84185-x

Cited by 15 publications

(15 citation statements)

References 87 publications

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“…For this reason, in this work we tried to analyze whether drug resistance in neuroblastoma cell lines is associated with a lack of p53 function and/or with TP53 mutations. Topoisomerase inhibitors (etoposide [30] and doxorubicin [31]) and DNA alkylating substances (cisplatin [32] and melphalan [33]) are chemotherapeutic agents currently administered to neuroblastoma patients. We used these drugs in our study, which we have performed with tolerable doses in vivo [4].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Assessment of the Role of p53 on Chemotherapy Treatments in Neuroblastoma Cell Lines

et al. 2021

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Neuroblastoma is the most frequent malignant extracranial solid tumor of infancy. The overall objective of this work consists of determining the presence of alterations in the p53/MDM2/p14ARF signaling pathway in neuroblastoma cell lines and deciphering their possible relationship with resistance to known antineoplastic drugs and to differentiation agents. Firstly, we characterized 10 neuroblastoma cell lines for alterations at the p53/MDM2/p14ARF signaling pathway by analysis of TP53 point mutations, MYCN and MDM2 amplification, and p14ARF methylation, homozygous deletions, and expression. Secondly, we chose SK-N-FI (mutated at TP53) and SK-N-Be(2) (wild-type TP53) cell lines, treated them with chemotherapeutic agents (doxorubicin, etoposide, cisplatin, and melphalan) and with two isomers of retinoic acid (RA): (9-cis and all-trans). Finally, we analyzed the distribution of the cell cycle, the induction of apoptosis, and the expression levels of p53, p21, and Bcl-2 in those two cell lines. P14ARF did not present promoter methylation, homozygous deletions, and protein expression in any of the 10 neuroblastoma cell lines. One TP53 point mutation was detected in the SK-N-FI cell line. MYCN amplification was frequent, while most cell lines did not present MDM2 amplification. Treatment of SK-N-FI and SK-N-Be(2) cells with doxorubicin, etoposide, cisplatin, and melphalan increased apoptosis and blocked the cycle in G2/M, while retinoic acid isomers induced apoptosis and decreased the percentage of cells in S phase in TP53 mutated SK-N-FI cells, but not in TP53 wild-type SK-N-Be(2) cells. Treatment with cisplatin, melphalan, or 9-cis RA decreased p53 expression levels in SK-N-FI cells but not in SK-N-Be (2). The expression of p21 was not modified in either of the two cell lines. Bcl-2 levels were reduced only in SK-N-FI cells after treatment with cisplatin. However, treatments with doxorubicin, etoposide, or 9-cis-RA did not modify the levels of this protein in either of the two cell lines. In conclusion, TP53 mutated SK-N-FI cells respond better to the retinoic isomers than TP53 wild-type SK-N-Be(2) cells. Although these are in vitro results, it seems that deciphering the molecular alterations of the p53/MDM2/p14ARF signaling pathway prior to treating patients of neuroblastoma might be useful for standardizing therapies with the aim of improving survival.

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Section: Discussionmentioning

confidence: 99%

In Vitro Assessment of the Role of p53 on Chemotherapy Treatments in Neuroblastoma Cell Lines

et al. 2021

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“…Comparably, in non-small cell lung cancer, MT2 upregulation was evident in patients following platinum therapy as well as in vivo murine models [131]. More recently, MT3 upregulation in neuroblastoma was correlated with refractory mechanisms to cisplatin [132]. Thus, inhibitors of the specific metallothionein may serve to diminish the cisplatin dose while maintaining its cytotoxic and genotoxic effects.…”

Section: Increased Cisplatin Detoxificationmentioning

confidence: 98%

Can Cisplatin Therapy Be Improved? Pathways That Can Be Targeted

Ali

Aouida

Sulaiman

et al. 2022

IJMS

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Cisplatin (cis-diamminedichloroplatinum (II)) is the oldest known chemotherapeutic agent. Since the identification of its anti-tumour activity, it earned a remarkable place as a treatment of choice for several cancer types. It remains effective against testicular, bladder, lung, head and neck, ovarian, and other cancers. Cisplatin treatment triggers different cellular responses. However, it exerts its cytotoxic effects by generating inter-strand and intra-strand crosslinks in DNA. Tumour cells often develop tolerance mechanisms by effectively repairing cisplatin-induced DNA lesions or tolerate the damage by adopting translesion DNA synthesis. Cisplatin-associated nephrotoxicity is also a huge challenge for effective therapy. Several preclinical and clinical studies attempted to understand the major limitations associated with cisplatin therapy, and so far, there is no definitive solution. As such, a more comprehensive molecular and genetic profiling of patients is needed to identify those individuals that can benefit from platinum therapy. Additionally, the treatment regimen can be improved by combining cisplatin with certain molecular targeted therapies to achieve a balance between tumour toxicity and tolerance mechanisms. In this review, we discuss the importance of various biological processes that contribute to the resistance of cisplatin and its derivatives. We aim to highlight the processes that can be modulated to suppress cisplatin resistance and provide an insight into the role of uptake transporters in enhancing drug efficacy.

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“…Then, 100 µM of CDDP or 200 µM of Elli in PBS was added topically directly onto each microtumor on the upper CAM and the eggs were left without movement for 30 min to enable absorption of CDDP/Elli to the microtumor and to avoid possible runoff from the microtumor sites. After that, the eggs were incubated for additional 24 h according to our previous study (15). At defined time-points, parts of the CAM, liver, lung, and brain were extracted to carry out additional analyses and to quantify the amount of human tumor cells that accumulated in the tissues using qPCR.…”

Section: In Ovo Chorioallantoic Membrane Assaymentioning

confidence: 99%

“…Chick embryo is characterized by its essential immunodeficiency during its embryonic life, which is not typical for mice that frequently do not allow induction and growth of all types of human cancers (8). The CAM assay is a well-established in vivo system to study the angiogenesis and the carcinogenesis of various tumors, including prostate cancer (9), glioblastoma (10), osteosarcoma (11), colon cancer (12), non-small cell lung cancer (13), thyroid cancer (14), or Nbl (15). For these purposes, both in ovo (16) and ex ovo (17) CAM assays have been employed for various purposes varying in experiments from protocol to protocol.…”

Section: Introductionmentioning

confidence: 99%

Extending the Applicability of In Ovo and Ex Ovo Chicken Chorioallantoic Membrane Assays to Study Cytostatic Activity in Neuroblastoma Cells

et al. 2021

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PurposeThe chick chorioallantoic membrane (CAM) assay can provide an alternative versatile, cost-effective, and ethically less controversial in vivo model for reliable screening of drugs. In the presented work, we demonstrate that CAM assay (in ovo and ex ovo) can be simply employed to delineate the effects of cisplatin (CDDP) and ellipticine (Elli) on neuroblastoma (Nbl) cells in terms of their growth and metastatic potential.MethodsThe Nbl UKF-NB-4 cell line was established from recurrent bone marrow metastases of high-risk Nbl (stage IV, MYCN amplification, 7q21 gain). Ex ovo and in ovo CAM assays were optimized to evaluate the antimetastatic activity of CDDP and Elli. Immunohistochemistry, qRT-PCR, and DNA isolation were performed.ResultsEx ovo CAM assay was employed to study whether CDDP and Elli exhibit any inhibitory effects on growth of Nbl xenograft in ex ovo CAM assay. Under the optimal conditions, Elli and CDDP exhibited significant inhibition of the size of the primary tumor. To study the efficiency of CDDP and Elli to inhibit primary Nbl tumor growth, intravasation, and extravasation in the organs, we adapted the in ovo CAM assay protocol. In in ovo CAM assay, both studied compounds (CDDP and Elli) exhibited significant (p < 0.001) inhibitory activity against extravasation to all investigated organs including distal CAM.ConclusionsTaken together, CAM assay could be a helpful and highly efficient in vivo approach for high-throughput screening of libraries of compounds with expected anticancer activities.

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Metallothionein-3 promotes cisplatin chemoresistance remodelling in neuroblastoma

Cited by 15 publications

References 87 publications

In Vitro Assessment of the Role of p53 on Chemotherapy Treatments in Neuroblastoma Cell Lines

In Vitro Assessment of the Role of p53 on Chemotherapy Treatments in Neuroblastoma Cell Lines

Can Cisplatin Therapy Be Improved? Pathways That Can Be Targeted

Extending the Applicability of In Ovo and Ex Ovo Chicken Chorioallantoic Membrane Assays to Study Cytostatic Activity in Neuroblastoma Cells

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