Inherent and Acquired Resistance to Paclitaxel in Hepatocellular Carcinoma

Molecular Events Involved

Avtar Meena, Aanchal Sharma, Ratna Kumari, Naoshad Mohammad, Shivendra Vikram Singh, Manoj Kumar Bhat

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and is a major cause of cancer related deaths worldwide. Only 10 to 20% of HCC can be surgically excised. Therefore, chemotherapeutic intervention and treatment is essential for achieving favorable prognosis. However, therapeutic outcome of chemotherapy is generally poor owing to inherent resistance of cancer cells to the treatment or due to development of acquired resistance. To differentiate and delineate the molecular events, we developed drug resistant Hep3B cells (DRC) by treating cells with the increasing concentration of paclitaxel. We also developed a unique single cell clone of Hep3B cells (SCC) by selecting single cell colonies and screening them for resistant phenotype. Interestingly, both DRC and SCC were resistant to paclitaxel in comparison to parental Hep3B cells. We analyzed the contributory factors that may be involved in the development of resistance. As expected, level of P-glycoprotein (P-gp) was elevated in DRC. In addition, Caveolin-1 (Cav-1), Fatty acid synthase (FASN) and Cytochrome P450 (CYP450) protein levels were elevated in DRC whereas in SCC, FASN and CYP450 levels were elevated. Downregulation of these molecules by respective siRNAs and/or by specific pharmacological inhibitors resensitized cells to paclitaxel. Interestingly, these drug resistant cells were also less sensitive to vinblastine, doxorubicin and methotrexate with the exception of cisplatin. Our results suggested that differential levels of P-gp, Cav-1 and FASN play a major role in acquired resistant phenotype whereas FASN level was associated with the presentation of inherent resistant phenotype in HCC.

Original languageEnglish (US)
Article numbere61524
JournalPloS one
Volume8
Issue number4
DOIs
StatePublished - Apr 16 2013

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paclitaxel
hepatoma
Paclitaxel
Fatty Acid Synthases
Hepatocellular Carcinoma
Caveolin 1
Pharmaceutical Preparations
fatty-acid synthase
P-Glycoprotein
Cytochrome P-450 Enzyme System
cells
Clone cells
drugs
Chemotherapy
Vinblastine
Methotrexate
Liver
Doxorubicin
Cisplatin
Phenotype

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Inherent and Acquired Resistance to Paclitaxel in Hepatocellular Carcinoma : Molecular Events Involved. / Meena, Avtar; Sharma, Aanchal; Kumari, Ratna; Mohammad, Naoshad; Singh, Shivendra Vikram; Bhat, Manoj Kumar.

In: PloS one, Vol. 8, No. 4, e61524, 16.04.2013.

Research output: Contribution to journalArticle

Meena, Avtar ; Sharma, Aanchal ; Kumari, Ratna ; Mohammad, Naoshad ; Singh, Shivendra Vikram ; Bhat, Manoj Kumar. / Inherent and Acquired Resistance to Paclitaxel in Hepatocellular Carcinoma : Molecular Events Involved. In: PloS one. 2013 ; Vol. 8, No. 4.
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