Sorafenib/Regorafenib and Lapatinib Interact to kill CNS Tumor Cells

Hamed, Hossein A.; Tavallai, Seyedmehrad; Grant, Steven; Poklepovic, Andrew; Dent, Paul

doi:10.1002/jcp.24689

Cited by 32 publications

(24 citation statements)

References 27 publications

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“…The (−)‐cananodine (as a rupestine analog) is proven to be five times more potent as a cytotoxic agent than the standard drug “sorafenib,” against HepG2 and HepG2.2.15 cell lines with IC 50 0.94 and 16.0 μM, respectively (Shelton, ). Sorafenib/Regorafeand and Lapatinib are commercial drugs used for the treatment of breast cancer and other solid tumors (Hamed, Tavallai, Grant, Poklepovic, & Dent, ).…”

Section: The Chemistry and Pharmacology Of Artemisia Alkaloids/alliedmentioning

confidence: 99%

The chemistry and pharmacology of alkaloids and allied nitrogen compounds fromArtemisiaspecies: A review

Rashid

Alamzeb²,

Ali³

et al. 2019

Phytotherapy Research

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Several reviews have been published on Artemisia's derived natural products, but it is the first attempt to review the chemistry and pharmacology of more than 80 alkaloids and allied nitrogen compounds obtained from various Artemisia species (covering the literature up to June 2018). The pharmacological potential and unique skeleton types of certain Artemisia's alkaloids provoke the importance of analyzing Artemisia species for bioactive alkaloids and allied nitrogen compounds. Among the various types of bioactive Artemisia's alkaloids, the main classes were the derivatives of rupestine (pyridine–sesquiterpene), lycoctonine (diterpene), pyrrolizidine, purines, polyamine, peptides, indole, piperidine, pyrrolidine, alkamides, and flavoalkaloids. The rupestine derivatives are Artemisia's characteristic alkaloids, whereas the rest are common alkaloids found in the family Asteraceae and chemotaxonomically links the genus Artemisia with the tribes Anthemideae. The most important biological activities of Artemisia's alkaloids are including hepatoprotective, local anesthetic, β‐galactosidase, and antiparasitic activities; treatment of angina pectoris, opening blocked arteries, as a sleep‐inducing agents and inhibition of HIV viral protease, CYP450, melanin biosynthesis, human carbonic anhydrase, [3H]‐AEA metabolism, kinases, and DNA polymerase β1. Some of the important nitrogen metabolites of Artemisia include pellitorine, zeatin, tryptophan, rupestine, and aconitine analogs, which need to be optimized and commercialized further.

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Section: The Chemistry and Pharmacology Of Artemisia Alkaloids/alliedmentioning

confidence: 99%

The chemistry and pharmacology of alkaloids and allied nitrogen compounds fromArtemisiaspecies: A review

Rashid

Alamzeb²,

Ali³

et al. 2019

Phytotherapy Research

View full text Add to dashboard Cite

show abstract

“…These alterations required a revision of the response assessment in neuro-oncology (RANO) criteria to include non-enhancing T2/fluid attenuated inversion recovery (FLAIR) lesions as a new criterion for glioma progression [7]. Regorafenib (REG) is a multikinase inhibitor that inhibits, amongst others, the vascular endothelial growth factor (VEGF) receptors 1-3 [8] and has shown efficacy in several cancers [9][10][11] as well as preclinical glioma models [12,13]. In the phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial for first recurrence of a glioblastoma, REG increased the median OS from 5.6 to 7.4 months compared to lomustine [14].…”

Section: Introductionmentioning

confidence: 99%

Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients

Zeiner

Kinzig

Divé

et al. 2019

JCM

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(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas. (2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients’ serum and CSF. (3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003). Diffusion restrictions were observed in 13 patients. (4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor.

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“…A recently completed Phase I trial demonstrated safety and preliminary data for activity in locally advanced extremity STS [ 24 ]. Regorafenib is a second generation multi-kinase inhibitor with activity and mechanism of action similar to sorafenib [ 25 ]. Regorafenib is approved for the treatment of metastatic colon cancer and advanced gastrointestinal stromal tumors [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma

et al. 2014

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BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 – 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 – 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-756) contains supplementary material, which is available to authorized users.

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Sorafenib/Regorafenib and Lapatinib Interact to kill CNS Tumor Cells

Cited by 32 publications

References 27 publications

The chemistry and pharmacology of alkaloids and allied nitrogen compounds fromArtemisiaspecies: A review

The chemistry and pharmacology of alkaloids and allied nitrogen compounds fromArtemisiaspecies: A review

Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma

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