Carboplatin: molecular mechanisms of action associated with chemoresistance

Sousa, Graziele Fonseca de; Wlodarczyk, Samarina Rodrigues; Monteiro, Gisele

doi:10.1590/s1984-82502014000400004

Cited by 97 publications

(78 citation statements)

References 49 publications

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“…Carboplatin also causes DNA damage, as it interacts with DNA and forming crosslinks in the DNA, that lead to inhibition of DNA synthesis and structural disruption. The configuration of the DNA is recognized by the mismatch repair (MMR) system that induces the expression of P53 and mediates the apoptosis pathway (Sousa et al 2014). Cancer cells can subvert these effects by the activation of the DNA damage response (DDR) to prevent apoptosis (Bonanno et al 2014).…”

Section: Dna Damage Responsementioning

confidence: 99%

“…Cancer cells resist carboplatin by increasing the expression of antiapoptotic genes and the loss of DNA MMR and decreasing pro-apoptotic factors, such as downregulation of P53 and caspase-9. Evidence shows that loss of MMR proteins is associated with drug resistance in ovarian cancer (Sousa et al 2014). MutP53 is also involved in the activation of various mechanisms relating to chemoresistance including promoting drug efflux, resistance to apoptosis signaling, activation of survival signals and upregulation of the DNA repair mechanism (He et al 2017).…”

Section: Dna Damage Responsementioning

confidence: 99%

“…Efflux pump proteins are transmembrane proteins that reduce intracellular drug accumulation by transporting Once cells become resistant to carboplatin, cross membrane transport of carboplatin becomes limited via rapid downregulation in the expression of CTR1, other transporters and cholesterol levels whereas cell membrane rigidity increases (Stewart 2007, Sousa et al 2014. A resistant cell increases levels of heavy metal detoxification proteins in its cytoplasm.…”

Section: Efflux Pump Proteinsmentioning

confidence: 99%

“…Platinum is chelated by glutathione (GSH). This conjugation is catalyzed by glutathione S-transferases (GSTs) and effluxes via an ATP-dependent mechanism, such as the glutathione S-conjugate export (GS-X) pump (Kelland 2007, Sousa et al 2014. The resistant cells also increase the sequestration of metals into lysosomes, mitigating the effects of platinum therapy (Holmes 2015, Zhitomirsky & Assaraf 2016 drug molecules out of the cell, thus decreasing their cytotoxic effects (Sauna & Ambudkar 2001).…”

Section: Efflux Pump Proteinsmentioning

confidence: 99%

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The potential role of miRNAs and exosomes in chemotherapy in ovarian cancer

Alharbi

Zúñiga

Elfeky

et al. 2018

Endocrine-Related Cancer

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Chemoresistance is one of the major obstacles in the treatment of cancer patients. It poses a fundamental challenge to the effectiveness of chemotherapy and is often linked to relapse in patients. Chemoresistant cells can be identified in different types of cancers; however, ovarian cancer has one of the highest rates of chemoresistance-related relapse (50% of patients within 5 years). Resistance in cells can either develop through prolonged cycles of treatment or through intrinsic pathways. Mechanistically, the problem of drug resistance is complex mainly because numerous factors are involved, such as overexpression of drug efflux pumps, drug inactivation, DNA repair mechanisms and alterations to and/or mutations in the drug target. Additionally, there is strong evidence that circulating miRNAs participate in the development of chemoresistance. Recently, miRNAs have been identified in exosomes, where they are encapsulated and hence protected from degradation. These miRNAs within exosomes (exo-miRNAs) can regulate

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Section: Dna Damage Responsementioning

confidence: 99%

Section: Dna Damage Responsementioning

confidence: 99%

Section: Efflux Pump Proteinsmentioning

confidence: 99%

Section: Efflux Pump Proteinsmentioning

confidence: 99%

See 2 more Smart Citations

The potential role of miRNAs and exosomes in chemotherapy in ovarian cancer

Alharbi

Zúñiga

Elfeky

et al. 2018

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…Like all the other platinum drugs, also carboplatin is metabo lized by GSTP1 and resistance can derive from increased levels and/or activity of this enzyme as well as from increased DNA damage repair and ABCC2 overexpression (Tables 2 & 4) [76,77].…”

Section: Carboplatinmentioning

confidence: 99%

Pharmacogenomics of Second-Line Drugs Used for Treatment of Unresponsive or Relapsed Osteosarcoma Patients

Hattinger¹,

Vella²,

Tavanti³

et al. 2016

Pharmacogenomics

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Second-line treatment of high-grade osteosarcoma (HGOS) patients is based on different approaches and chemotherapy protocols, which are not yet standardized. Although several drugs have been used in HGOS second-line protocols, none of them has provided fully satisfactory results and the role of rescue chemotherapy is not well defined yet. This article focuses on the drugs that have most frequently been used for second-line treatment of HGOS, highlighting the present knowledge on their mechanisms of action and resistance and on gene polymorphisms with possible impact on treatment sensitivity or toxicity. In the near future, validation of the so far identified candidate genetic biomarkers may constitute the basis for tailoring treatment by taking the patients' genetic background into account. Osteosarcoma is the most common tumor of bone, which can exibit different levels of malignancy [1,2]. High-grade osteo sarcoma (HGOS) is a very aggressive neoplasm that, in unselected populations, is responsible for death of approximately 40-50% of patients [2,3]. The subgroup of the so-called conventional HGOS includes patients with high-grade tumors located in the extremities, nonmetastatic at diagnosis and younger than 40 years [1]. In this subgroup of HGOS, prognosis is slightly better, reaching 60-65% when patients are treated with multiagent neoadjuvant chemotherapy [4][5][6].The major clinical problem limiting the cure rate of HGOS patients is relapse, which in most cases consists in development of lung metastasis within the first 24-36 months from diagnosis [7,8]. Treatment of relapsed HGOS is based on different approaches and second-line chemotherapy protocols which, however, are not standardized and can rescue no more than 20-25% of patients [4,5]. Methods of data searching & selectionA systematic literature search was performed using 'treatment' and 'osteosarcoma' as key words in PubMed [9]. We further restricted the selection to studies performed in humans. By using all the aforementioned different combinations and selections, the literature searches revealed a total of 13,976 results. The key terms 'polymorphism', 'toxicity', 'drug response', 'drug resistance', 'pharmaco genetic', 'pharmacogenomic', 'epigenetic', 'methylation' and 'clinical trial' were then used to refine the results of the previous search, in order to select the publications which were strictly related to each section of this review. Full-length articles and reviews in English were taken into consideration.Only drugs used in at least two different clinical trials with published results were included in this review and, consequently, we considered genes and gene poly morphisms with possible relevance for response and/or

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Applications of Biodegradable Polymers in the Encapsulation of Anticancer Metal Complexes

Redrado,

Xiao,

Upitak

et al. 2024

Adv Funct Materials

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Metal complexes have recently attracted a lot of attention, particularly as anticancer and antibacterial agents, owing to their versatile mechanisms and easily tunable characteristics. However, the application of such compounds in a medical context, especially in cancer treatment, has been hampered due to their limited solubility and stability in water and aqueous solutions, as well as a lack of selectivity. To address these limitations, several approaches have been developed to improve the targeted delivery of these compounds and their solubility. The first strategy involves the physical encapsulation of these metal complexes within carriers to facilitate controlled drug release. The second strategy involves covalently linking metal complexes to polymers, creating prodrugs that can be converted to active drugs at a more controllable rate. Despite the increasing variety of polymers available, the need to develop those able to be metabolized by the body, producing non‐toxic residues, remains crucial for effective treatment, particularly in the area of diseases such as cancer. In this perspective article, an overview of recent developments in the encapsulation of metal complexes using biodegradable polymers for cancer therapy is provided. It is specifically highlighting how the formed nanoparticles (NPs) enhance the selectivity and toxicity toward cancer cells compared to the parent metal complex, while simultaneously reducing the harmful side effects of traditional chemotherapies, opening the door for using them in combination therapies (PDT, PTT).

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Carboplatin: molecular mechanisms of action associated with chemoresistance

Cited by 97 publications

References 49 publications

The potential role of miRNAs and exosomes in chemotherapy in ovarian cancer

The potential role of miRNAs and exosomes in chemotherapy in ovarian cancer

Pharmacogenomics of Second-Line Drugs Used for Treatment of Unresponsive or Relapsed Osteosarcoma Patients

Applications of Biodegradable Polymers in the Encapsulation of Anticancer Metal Complexes

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