MyMedR

Displaying all 4 publications

Abstract:

Sort:

Targeting oncogenes and tumor suppressors genes to mitigate chemoresistance

Fatemian T, Chowdhury EH

Curr Cancer Drug Targets, 2014;14(7):599-609.
PMID: 25308718

Malfunctions in membrane transporters or disruptions in signaling cascades induce resistance to chemotherapy in cancer cells resulting in treatment failure. To adjust the genetic alterations leading to these cellular protective measures, dissection and verification of the contributing routes would be required. In justification of knockdown of the key genes, RNA interference provides a reliable probing tool, enabling exploration of phenotypic manifestation of targeted genes. Investigation of the non-transporter targets, predominantly oncogenes and tumor suppressor genes, by means of small interfering RNA with the aim to re-sensitize cancer cells to therapeutics will be discussed in this review.
Strategies and validation for siRNA-based therapeutics for the reversal of multi-drug resistance in cancer

Fatemian T, Othman I, Chowdhury EH

Drug Discov Today, 2014 Jan;19(1):71-8.
PMID: 23974068 DOI: 10.1016/j.drudis.2013.08.007

Resistance of cancer cells to anticancer drugs is the main reason for the failure of traditional cancer treatments. Various cellular components and different loops within the signaling pathways contribute to drug resistance which could be modulated with the aim to restore drug efficacy. Unveiling the molecular mechanisms for cancer drug resistance has now paved the way for the development of novel approaches to regulate the response rates to anticancer drugs at the genetic level. The recent progress on identification and validation of the vital genes directly or indirectly involved in development of cancer drug resistance with the aid of the specific knock down ability of RNA interference technology is discussed in this review.
Fulltext Intracellular Delivery of siRNAs Targeting AKT and ERBB2 Genes Enhances Chemosensitization of Breast Cancer Cells in a Culture and Animal Model

Fatemian T, Moghimi HR, Chowdhury EH

Pharmaceutics, 2019 Sep 03;11(9).
PMID: 31484456 DOI: 10.3390/pharmaceutics11090458

: Pharmacotherapy as the mainstay in the management of breast cancer suffers from various drawbacks, including non-targeted biodistribution, narrow therapeutic and safety windows, and also resistance to treatment. Thus, alleviation of the constraints from the pharmacodynamic and pharmacokinetic profile of classical anti-cancer drugs could lead to improvements in efficacy and patient survival in malignancies. Moreover, modifications in the genetic pathophysiology of cancer via administration of small nucleic acids might pave the way towards higher response rates to chemotherapeutics. Inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized in this study to efficiently deliver various classes of therapeutics into cancer cells. Co-delivery of drugs and genetic materials was successfully attained through a carbonate apatite delivery device. On 4T1 cells, siRNAs against AKT and ERBB2 plus paclitaxel or docetaxel resulted in the largest increase in anti-cancer effects compared to CA/paclitaxel or CA/docetaxel. Therefore, these ingredients were selected for further in vivo investigations. Animals receiving injections of CA/paclitaxel or CA/docetaxel loaded with siRNAs against AKT and ERBB2 possessed significantly smaller tumors compared to CA/drug-treated mice. Interestingly, synergistic interactions in target protein knock down with combinations of CA/AKT/paclitaxel, CA/ERBB2/docetaxel were documented via western blotting.
Fulltext Knockdown of PLC-gamma-2 and calmodulin 1 genes sensitizes human cervical adenocarcinoma cells to doxorubicin and paclitaxel

Stanislaus A, Bakhtiar A, Salleh D, Tiash S, Fatemian T, Hossain S, et al.

Cancer Cell Int, 2012 Jun 18;12(1):30.
PMID: 22709569 DOI: 10.1186/1475-2867-12-30

BACKGROUND: RNA interference (RNAi) is a powerful approach in functional genomics to selectively silence messenger mRNA (mRNA) expression and can be employed to rapidly develop potential novel drugs against a complex disease like cancer. However, naked siRNA being anionic is unable to cross the anionic cell membrane through passive diffusion and therefore, delivery of siRNA remains a major hurdle to overcome before the potential of siRNA technology can fully be exploited in cancer. pH-sensitive carbonate apatite has recently been developed as an efficient tool to deliver siRNA into the mammalian cells by virtue of its high affinity interaction with the siRNA and the desirable size distribution of the resulting siRNA-apatite complex for effective cellular endocytosis. Moreover, internalized siRNA was found to escape from the endosomes in a time-dependent manner and efficiently silence gene expression.
RESULTS: Here we show that carbonate apatite-mediated delivery of siRNA against PLC-gamma-2 (PLCG2) and calmodulin 1 (CALM1) genes has led to the sensitization of a human cervical cancer cell line to doxorubicin- and paclitaxel depending on the dosage of the individual drug whereas no such enhancement in cell death was observed with cisplatin irrespective of the dosage following intracellular delivery of the siRNAs.
CONCLUSION: Thus, PLCG2 and CALM1 genes are two potential targets for gene knockdown in doxorubicin and paclitaxel-based chemotherapy of cervical cancer.