CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2022; 43(S 01): S1-S19
DOI: 10.1055/s-0042-1755494
Abstracts

Autophagy Inhibition Invoke Resistance to Arsenic Trioxide Induced Apoptosis in Acute Promyelocytic Leukemia

Deepshikha Dutta
1   Hasan Lab, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
2   Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
,
Bhausaheb Bagal
3   Department of Medical Oncology, Tata Memorial Hospital Mumbai, India
,
Hasmukh Jain
3   Department of Medical Oncology, Tata Memorial Hospital Mumbai, India
,
Syed K. Hasan
1   Hasan Lab, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
2   Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
› Author Affiliations
› Further Information
 

Correspondence to: shasan@actrec.gov.in

Background: Despite significant advances in the management of acute promyelocytic leukemia (APL), 10 to 20% of de novo and 30 to 50% of relapsed patients show resistance toward arsenic trioxide (ATO) therapy. To investigate factors contributing ATO resistance using ATO sensitive and resistant APL cell model system, we examined the role of autophagy in ATO resistance.

Materials and Methods: PML-RARA positive ATO sensitive and resistant NB4 cell lines (NB4S and NB4R) and ATO (INTAS pharmaceuticals). IC50 by CTG assay and synergy calculation using Calcusyn. Apoptosis assays by flow cytometry. The qRT-PCR and western blots for transcripts and protein levels were studied.

Results: The IC50 of ATO was found to be 3.8 times higher in NB4R compared to NB4S cells (0.72µMvs2.77µM). Flow cytometry data showed higher rate of apoptosis in sensitive than resistant cells (50 vs. 18% at 4µMATO). The protein levels of autophagy markers (p62, LC3-I/II) in NB4R remained unchanged at higher ATO concentrations. Levels of p62 were decreased 90% in dose dependent manner in NB4S cells. Conversion of LC3 I to II on ATO treatment was found abysmal in NB4R cells suggesting autophagy inhibition. Interestingly, 3µMATO eradicated PML-RARA protein in NB4S cells but failed to conduct in NB4R cells suggesting that degradation of PML-RARA in ATO sensitive cells is mediated through autophagy.

Conclusion: Preliminary data highlight the role of autophagy inhibition in resistance to ATO induced apoptosis leading to reduced degradation of PML-RARA.



Publication History

Article published online:
22 August 2022

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