Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/EZH2

Background: Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide. Cancer development and progression require inactivation of tumor suppressor genes and activation of proto-oncogenes. The well recognized mechanism of action demonstrated for chemotherapeutic agents is induction of apoptosis via reactivation of p53. In this context, we evaluate the efficacy of IV and oral routes of our novel PH and temperature sensitive doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NP) in affecting p53 profile in an OSCC rat model. Methods: In this study, 120 male rats were divided into 8 groups of 15 animals each. The new formulated DOX-MTX NP and free doxorubicin were IV and orally given to rats with 4-nitroquinoline-1-oxide induced OSCC. Results: Results showed that both DOX and DOX-MTX-NP caused significant increase in mRNA levels of P53 compared to the untreated group (p<0.000). With both DOX and DOX-MTX NP, the IV mode was more effective than the oral (gavage) route (p<0.000). Surprisingly, in oral mode, p53 mRNA was not affected in DOX treated groups (p>0.05), Nonetheless, both IV and oral administration of MTX-DOX NP showed superior activity (~3 fold) over free DOX in reactivation of p53 in OSCC (p<0.000). The effectiveness of oral route in group treated with nanodrug accounts for the enhanced bioavailability of nanoparticulated DOX-MTX compared to free DOX. Moreover, in treated groups, tumor stage was markedly related to the amount of p53 mRNA (p<0.05). Conclusion: Both oral and IV application of our novel nanodrug possesses superior activity over free DOX-in up-regulation of p53 in a OSCC model and this increase in p53 level associated with less aggressive tumors in our study. Although, impressive results obtained with IV form of nanodrug (-21 fold increase in p53 mRNA level) but both forms of nanodrug are effective in OSCC, with less toxicity normal cells.

Section: Comparison Between Efficacy Of Oral and IV Treatment Of Ratsmentioning

confidence: 92%

DOX-MTX-NPs Augment p53 mRNA Expression in OSCC Model in Rat: Effects of IV and Oral Routes

Abbasi¹,

Khiavi²,

Amir³

et al. 2014

“…The main mechanism of action described for DOX and MTX is induction of apoptosis via activation / increase in p53 level (Huang et al, 2011;Tacar et al, 2013), In our earlier study (data not published), we observed remarkable increase in p53 mRNA level after treatment of cancerous group with oral and IV forms of DOX and DOX-MTX NPs , However both oral and IV forms of DOX-MTX NP showed superior performance over DOX in increasing p53 amount (Mesgari Abbasi et al, 2014a). To our knowledge, this is the first record that a new formulation of Doxorubicin possesses anti-MMP activity besides its enhanced apoptotic potential in the new format, whilst such a potential has never described for free DOX.…”

Section: Discussionmentioning

confidence: 74%

“…In other side,Methotrexate (MTX) is another central chemotherapeutic drug that is widely used either in monotherapy or in combination with other biologic and synthetic disease modifying anti cancer drugs (Huang et al, 2011;Cipriani et al, 2014) .…”

Section: Introductionmentioning

confidence: 99%

Oral and IV Dosages of Doxorubicin-Methotrexate loaded-Nanoparticles Inhibit Progression of Oral Cancer by Down-Regulation of Matrix Methaloproteinase 2 Expression in Vivo

Abbasi¹,

Jahanban‐Esfahlan²,

Amir³

et al. 2015

Asian Pac J Cancer Prev, 15 (24), 10705-10711 IntroductionSquamous cell carcinomas encompass approximately 95% of all oral malignancies. Oral cancer holds the sixth position in cancer incidence ranking worldwide (Albano et al., 2013;Baykara et al., 2013). Squamous cell carcinoma (SSC) of the tongue has historically been shown to be associated with a poor prognosis , much more an aggressive biological and clinical behavior and a high metastatic potential (Jones et al., 1992; BrandweinGensler et al., 2005;Kademani et al., 2005;Bell et al., 2007;Montoro et al., 2008). Patients with premalignant lesions and early stage cancers have a high rate of survival, but the vast majority of Stages III and IV cases are fatal (Zwetyenga et al., 2003;Massano et al., 2006;Montoro et al., 2008).The prognosis of SCC depends on a series of factors such as proliferative activity of the tumor,

“…Cytotoxic effect of Doxorubicin most often attributed to its potential in induction of apoptosis by recruiting divergent targets as well as p53 (Gibson et al, 2005;Huang et al, 2011). However to our knowledge there is no record for Doxorubicin induced HER2 mRNA down-regulation in tumors, nonetheless in our study, none of oral and IV forms of DOX influenced the HER2 mRNA level in treated groups, surprisingly both forms of the new formulated DOX (DOX-MTX NP) showed high performance in affecting HER2 mRNA level and interestingly this decrease in HER2 paralleled with less aggressive tumors in this group.…”

Section: Discussionmentioning

confidence: 99%

New formulated "DOX-MTX-loaded Nanoparticles" Down-regulate HER2 Gene Expression and Improve the Clinical Outcome in OSCCs Model in Rat: the Effect of IV and Oral Modalities

Abbasi

Amir²,

Hamishehkar³

et al. 2014

Background: Oral squamous cell carcinoma (OSCC) remains as one of the most difficult malignancies to control because of its high propensity for local invasion and cervical lymph node dissemination. In this study, we evaluate the efficacy of our novel pH and temperature sensitive doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NP) in affecting HER2 expression profile in OSCC model in rat. Results: DOX-MTX-nanoparticle complexes caused significant decrease in mRNA level of HER2 compared to untreated cancers (p<0.05) and this finding was more pronounced with the IV mode (p<0.000). Surprisingly, HER2 mRNA was not affected in DOX treated as compared to the control group (p>0.05). On the other hand, in the DOX-MTX NP treated group, fewer tumors characterized with advanced stage and decreased HER2 paralleled improved clinical outcome (P<0.05). Moreover, the effectiveness of the oral route in the group treated with nanodrug accounted for the enhanced bioavailability of nanoparticulated DOX-MTX compared to free DOX. Furthermore, there was no significant difference in mRNA level of HER2 (p>0.05). Conclusions: Influence of HER2 gene expression is a new feature and mechanism of action observed only in dual action DOX-MTX-NPs treated groups. Down-regulation of HER2 mRNA as a promising marker and prognosticator of OSCC adds to the cytotoxic benefits of DOX in its new formulation. Both oral and IV application of this nanodrug could be used, with no preferences in term of their safety or toxicity. As HER2 is expressed abundantly by a wide spectrum of tumors, i DOX-MTX NPs may be useful for a wide-spectrum of lesions. However, molecular mechanisms underlying HER2 down regulation induced by DOX-MTX NPs remain to be addressed.