HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review).

Heat shock protein 90 (HSP90) is a vital chaperone protein, regulating signaling pathways and correcting misfolded proteins in cancer cells by interacting with oncogenic client proteins and co­chaperones. The inhibition of HSP90 chaperone machinery has been demonstrated as a potential approach with which to inhibit tumor survival, proliferation, invasion and migration. Numerous HSP90 inhibitors have been reported and have exhibited value as cancer­targeted therapies by interrupting the ATPase activity of HSP90, thus suppressing the oncogenic pathways in cancer cells. These inhibitors have been classified into three categories: i) N­terminal domain (NTD) inhibitors; ii) C­terminal domain (CTD) inhibitors; and iii) isoform­selective inhibitors. However, none of these HSP90 inhibitors are used as clinical treatments. The major limiting factors can be summarized into drug resistance, dose­limiting toxicity and poor pharmacokinetic profiles. Novel HSP90­targeted compounds are constantly being discovered and tested for their antitumor efficacy in preclinical and clinical trials, highlighting the prospect of the use of HSP90 inhibitors as cancer­targeted therapies. Additionally, improved antitumor effects have been observed when HSP90 inhibitors are used in combination with chemotherapy, targeted agents, or immunotherapy. In the present review, the effects of HSP90 inhibitors on the management of the cancer process are discussed and previous and novel HSP90­based therapeutic strategies in cancer treatment are summarized. Furthermore, prospective HSP90­targeting candidates are proposed for their future evaluation as cancer treatments.

Effects of lanthanum nitrate on behavioral disorder, neuronal damage and gene expression in different developmental stages of Caenorhabditis elegans.

Rare earth elements (REEs) are widely used in the industry, agriculture, biomedicine, aerospace, etc, and have been shown to pose toxic effects on animals, as such, studies focusing on their biomedical properties are gaining wide attention. However, environmental and population health risks of REEs are still not very clear. Also, the REEs damage to the nervous system and related molecular mechanisms needs further research. In this study, the L1 and L4 stages of the model organism Caenorhabditis elegans were used to evaluate the effects and possible neurotoxic mechanism of lanthanum(III) nitrate hexahydrate (La(NO3)3·6H2O). For the L1 and L4 stage worms, the 48-h median lethal concentrations (LC50s) of La(NO3)3·6H2O were 93.163 and 648.0 mg/L respectively. Our results show that La(NO3)3·6H2O induces growth inhibition and defects in behavior such as body length, body width, body bending frequency, head thrashing frequency and pharyngeal pumping frequency at the L1 and L4 stages in C. elegans. The L1 stage is more sensitive to the toxicity of lanthanum than the L4 stage worms. Using transgenic strains (BZ555, EG1285 and NL5901), we found that La(NO3)3·6H2O caused the loss or break of soma and dendrite neurons in L1 and L4 stages; and α-synuclein aggregation in L1 stage, indicating that Lanthanum can cause toxic damage to dopaminergic and GABAergic neurons. Mechanistically, La(NO3)3·6H2O exposure inhibited or activated the neurotransmitter transporters and receptors (glutamate, serotonin and dopamine) in C. elegans, which regulate behavior and movement functions. Furthermore, significant increase in the production of reactive oxygen species (ROS) was found in the L4 stage C. elegans exposed to La(NO3)3·6H2O. Altogether, our data show that exposure to lanthanum can cause neuronal toxic damage and behavioral defects in C. elegans, and provide basic information for understanding the neurotoxic effect mechanism and environmental health risks of rare earth elements.

BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and 30% of patients with CRC experience metastasis. Patients with metastatic colorectal cancer (mCRC) have a 5-year overall survival rate of <10%. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations are mostly studied in mCRC, as clinical trials found that first-line chemotherapy with anti-epidermal growth factor receptor agent confers limited efficacy for mCRC. Treatment decisions for early-stage mCRC do not consider BRAF or KRAS mutations, given the dramatically poor prognosis conferred by these mutations in clinical trials. Thus, it is necessary to identify patients with mCRC harboring BRAF or KRAS mutations to formulate rational therapeutic strategies to improve prognosis and survival. BRAF and KRAS mutations occur in ∼10% and ∼44% of patients with mCRC, respectively. Although the survival rate of patients with mCRC has improved in recent years, the response and prognosis of patients with the aforementioned mutations are still poor. There is a substantial unmet need for prospective personalized therapies for patients with BRAF- or KRAS-mutant mCRC. In this review, we focus on BRAF and KRAS mutations to understand the mechanisms underlying resistance and improving the response rate, outcomes, and prognosis of patients with mCRC bearing these mutations and to discuss prospective personalized therapies for BRAF- and KRAS-mutant mCRC.