Platinum-based chemotherapy in advanced non-small-cell lung cancer: optimal number of treatment cycles

Rossi, Antonio; Maïo, Massimo Di

doi:10.1586/14737140.2016.1170596

Cited by 175 publications

(138 citation statements)

References 56 publications

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“…Although platinum-based drugs are often considered “old-fashioned”, these compounds are still of high importance for most treatment regimen in lung cancer therapy [6, 7]. Regardless, the overall response is quite low (around 20%) and—despite several dose and combination studies—the 1-year survival rate has only increased to around 25–30% during the last decades [8]. The reason for this unsatisfactory performance is that treatment has to be frequently discontinued due to drug resistance development [9] or severe side effects like nephrotoxicity, neurotoxicity and ototoxicity for cisplatin or myelosuppression for carboplatin [10].…”

Section: Introductionmentioning

confidence: 99%

EGFR-targeting peptide-coupled platinum(IV) complexes

et al. 2017

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The high mortality rate of lung cancer patients and the frequent occurrence of side effects during cancer therapy demonstrate the need for more selective and targeted drugs. An important and well-established target for lung cancer treatment is the occasionally mutated epidermal growth factor receptor (EGFR). As platinum(II) drugs are still the most important therapeutics against lung cancer, we synthesized in this study the first platinum(IV) complexes coupled to the EGFR-targeting peptide LARLLT (and the shuffled RTALLL as reference). Notably, HPLC–MS measurements revealed two different peaks with the same molecular mass, which turned out to be a transcyclization reaction in the linker between maleimide and the coupled cysteine moiety. With regard to the EGFR specificity, subsequent biological investigations (3-day viability, 14-day clonogenic assays and platinum uptake) on four different cell lines with different verified EGFR expression levels were performed. Unexpectedly, the results showed neither an enhanced activity nor an EGFR expression-dependent uptake of our new compounds. Consequently, fluorophore-coupled peptides were synthesized to re-evaluate the targeting ability of LARLLT itself. However, also with these molecules, flow cytometry measurements showed no correlation of drug uptake with the EGFR expression levels. Taken together, we successfully synthesized the first platinum(IV) complexes coupled to an EGFR-targeting peptide; however, the biological investigations revealed that LARLLT is not an appropriate peptide for enhancing the specific uptake of small-molecule drugs into EGFR-overexpressing cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s00775-017-1450-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

EGFR-targeting peptide-coupled platinum(IV) complexes

et al. 2017

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“…Platinum-based chemotherapies are still the firstline regimens in the treatment of NSCLC cases with no targetable genetic mutations [21,22]. Patients are administered with four-six cycles [22] of platinumbased chemotherapy, which normally consists of a platinum compound such as cisplatin (cis-Pt) or carboplatin administered alongside a third-generation chemotherapeutic agent [10,12,21,22]. In the clinic, the taxane-platinum combinations are the standard of care treatments of advanced NSCLC [14,23].…”

Section: Research Papermentioning

confidence: 99%

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2020

Oncotarget

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Platinum-taxane combination chemotherapy still represents the standard of care for advanced non-small cell lung cancer (NSCLC) with no targetable driver mutations. However, the efficacy of these drugs has plateaued at 10-14 months primarily due to dose-limiting toxicity, chemoresistance, and metastasis. Here, we explored the effects of withaferin A (WFA) alone and in combination with paclitaxel (PAC) on the growth, proliferation, migration, and invasion of human NSCLC cells. We show that the sensitivity of H1299 and A549 cells to concomitant treatment with PAC and WFA was greater than that of either PAC or WFA alone. Using the combination index and dosereduction index, we demonstrated that various combinations (1:40, 1:20, 1:10) of PAC to WFA, respectively, were highly synergistic. In addition, PAC+WFA co-treatment synergistically inhibited colony formation, migration, invasion and increased the induction of apoptosis in H1299 and A549 cells. Interestingly, the synergism of PAC and WFA was not schedule-dependent but was enhanced when cells were pretreated with WFA indicating a chemo-sensitizing effect. Importantly, WFA was active against both PAC-sensitive (TS-A549) and PAC-resistant (TR-A549) cells both in vitro and in vivo. Mechanistically, WFA inhibits the proliferation of NSCLC cells via thiol oxidation. The effects of WFA were inhibited in the presence of N-acetyl cysteine and other thiol donors. Taken together, our results demonstrate the efficacy of WFA alone or alongside PAC on NSCLC cells and provide a strong rationale for further detailed testing in clinically relevant models for the development of PAC+WFA combination as an alternative therapeutic strategy for advanced NSCLC.

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“…[15] Cisplatin-based adjuvant chemotherapy remains the gold standard in NSCLC therapy. [16] In this work, the therapeutic efficacyo f1a was investigated using nude mice implanted with NCI-H460 NSCLC cells (Figure 1b and Figure S8 a). Tr eatment of the mice with 1a (20 mg kg À1 ) by intravenous injection two to three times per week inhibited tumor growth by 70 %.…”

Section: Hnmr and Esi-ms Analysis (Figures S2 And S3) Thea Bsorptionmentioning

confidence: 99%

An Antitumor Bis(N‐Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target

Yang

Lok

et al. 2019

Angewandte Chemie

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New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe arare example of an antitumor Pt II complex targeting at umor-associated protein, rather than DNA, under cellular conditions.Complex [(bis-NHC)Pt(bt)]PF 6 (1a;H bt = 1-(3-hydroxybenzo-[b]thiophen-2-yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry.Anunbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as am olecular target of 1a.A ccordingly, 1a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. Ab is-NHC-ligated Pt species generated from the hydrolysis of 1a forms adducts with thiols and appears to target an active-site cysteine of ASNS.

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Platinum-based chemotherapy in advanced non-small-cell lung cancer: optimal number of treatment cycles

Cited by 175 publications

References 56 publications

EGFR-targeting peptide-coupled platinum(IV) complexes

EGFR-targeting peptide-coupled platinum(IV) complexes

Untitled

An Antitumor Bis(N‐Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target

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