Background: Chemoresistance is a prevalent issue in cancer treatment.
Paclitaxel (PTX), a microtubule-binding anticancer drug, often exhibits
chemoresistance due to P-glycoprotein (Pgp), a drug efflux pump. It has also
been observed that overexpressed T-type calcium (Ca2+) channels
(TTCCs) maintain Ca2+ homeostasis in cancer cells, contributing to
chemoresistance.
Aim: This study aims to investigate the adjuvant role of TTA-A2, a
TTCC blocker, in enhancing the anticancer effects of PTX on the A549 lung
adenocarcinoma cell line.
Methods: Morphology assay, Ca2+ imaging, clonogenic
assay, apoptosis assay, and real-time PCR were performed. Samples were treated
with 10 nM PTX and TTA-A2 at 50 nM and 100 nM, including a combination of 10 nM
PTX and 100 nM TTA-A2.
Results and Conclusion: Immunocytochemistry and real-time PCR
confirmed Cav3.1 and Cav3.2 (TTCC isoforms) expression, with higher Cav3.2
levels. The morphology assay showed no differences among treatment groups. The
adjuvant effects of TTA-A2 were seen in Ca2+ imaging, clonogenic,
and apoptosis assays. In the Ca2+ imaging assay, a significant
reduction in the 340/380 ratio was seen in combination treatment with
spheroids. The clonogenic assay showed the minimum number of colonies in the
combination treatment. Similarly, the apoptosis assay showed the highest number
of PI-stained (dead) cells in the combination treatment in both monolayer and
spheroids. Furthermore, no significant changes in the Pgp mRNA expression were
observed in real-time PCR in any treatment group, indicating that PTX and
TTA-A2 treatment does not significantly alter Pgp expression. Since cancer
cells show resistance to PTX through Pgp activity and TTA-A2 is not a substrate
of Pgp, a combination of a reduced PTX concentration and TTA-A2 treatment may
prove to be a more effective cancer treatment. Overall, our results indicated
an adjuvant role of TTA-A2 in combination with PTX, which can help in
overcoming chemoresistance and provide better cancer treatment.
Author(s)
Details
Neema
Kumari
Regenerative Stem Cells Laboratory, Department of Biomedical
Engineering, Indian Institute of Technology Hyderabad, Sangareddy, 502284,
Telangana, India, Department of Biotechnology, Indian Institute of Technology
Hyderabad, Sangareddy, 502284, Telangana, India and Department of Microbiology,
Malla Reddy Institute of Medical Sciences, Suraram, Hyderabad, 500055,
Telangana, India.
Pravin
Shankar Giri
Regenerative Stem Cells Laboratory, Department of Biomedical
Engineering, Indian Institute of Technology Hyderabad, Sangareddy, 502284,
Telangana, India.
Subha
Narayan Rath
Regenerative Stem Cells Laboratory, Department of Biomedical
Engineering, Indian Institute of Technology Hyderabad, Sangareddy, 502284,
Telangana, India.
Please see the book here:- https://doi.org/10.9734/bpi/mmrnp/v3/1813
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