Page 44 - ebook

Improving the efficacy of oncolytic virus

in doxorubicin-resistant ovarian cancer

Seoyul Lee, DaeKyoung Kim, MinJoo Shin, YeEun Kim, Hojun Kim, Migyeon Choi, and JaeHo Kim
Department of Physiology, School of Medicine, Pusan National University, Yangsan- si,50612

A A
Abstract GFP OVV (TK - GFP + ) 10 STAT3/p-STAT3
GFP A2780 A2780-R
inhibitor D 8
Thymidine Kinase TK STAT3
Recurrent ovarian cancer is caused by TK deletion 6
drug-resistant cancer cells after chemotherapy. To B A2780 A2780-R A2780 A2780-R p-STAT3 4
overcome recurrent ovarian cancer, it needs to GAPDH 2
develop anti-cancer treatments to eradicate 0
drug-resistant cancer cells. In this study, we inhibitor D A2780 A2780-R
isolated a drug-resistant cell line of A2780 ovarian B C
cancer cells by subculture in the presence of 70 35
Doxorubicin. The Doxorubicin-resistant A2780 60 30
cells (A2780-R) exhibited higher resistance to 50 25
Doxorubicin than A2780 cells. We next 24hr 48hr 40 20
15
30
investigated the possibility of an oncolytic vaccine C A2780 A2780-R 20 10
virus (OVV) for the death of conventional 37% 8% 100 A2780 10 5
A2780-R
chemotherapy-resistant cells. Interestingly, 24hr 80 0 0
A2780-R cells exhibited reduced virus replication 60 inhibitor D inhibitor D
STAT3i
STAT3i
and cell death compared to A2780 cells. Several 40 A2780 + V A2780-R + V A2780 + V A2780-R + V
signaling mechanisms were changed in A2780-R 83% 36% 20 D
compared to A2780 cells. In treating inhibitors for 48hr only V V + inhibitor D V + STAT3i V + inhibitor D + STAT3i
these signaling factors, inhibitor D increased the 0 24 48
replication of OVV and cell death in A2780-R cells. Hours post infection
In addition, the phosphorylation of STAT3 was D GFP
increased during inhibitor D treatment, and the A2780 11% A2780-R 4%
increase in OVV replication by inhibitor D 80 A2780
A2780-R
treatment was abrogated during treatment of a 24hr 60
STAT3 inhibitor. These results suggest that the 40
pharmacological attenuation of the target signal
by inhibitor D augments the oncolytic efficacy of 60% 12% 20 Figure 4. Phosphorylation of STAT3 through inhibitor D
OVV in drug-resistant ovarian cancer. 48hr treatment promotes viral replication in drug-resistant
0
24 48 cancer cells
Hours post infection
7-AAD
Results Figure 2. A2780-R cells resisted to oncolytic vaccinia Conclusion
virus than A2780 cells
A B A This study showed that the inhibition of target
5 signaling in cancer cells could promote the viral
A2780 4
3 replication and oncolytic effect in cancer cells.
+ Doxorubicin 2 This suggests that combined treatment with
1 approved inhibitors in clinical trials of OVV may
0
Acquired resistance
5 enhance the treatment effects to patients.
4
3
2
A2780-R 1
0 Reference
C D
A2780 A2780-R
C D E
35 ns 16 ns 5 only V
0.4% 39.1% ns V + inhibitor D 1. Heo, J., et al., Randomized dose-finding
ABCB1 30 4
25 12 clinical trial of oncolytic immunotherapeutic
ABCG2 20 3
8 vaccinia JX-594 in liver cancer. Nat Med,
ALDH1 15 2
GAPDH 10 4 1 2013. 19(3): p. 329-36.
5
ALDH-FITC ALDH-FITC 0 0 0 2. Vasan, N., J. Baselga, and D.M. Hyman, A view
E inhibitor D inhibitor D on drug resistance in cancer. Nature, 2019.
100 120 A2780-R + V A2780-R + V 575(7782): p. 299-309.
80 100 F TMSC A2780 A2780-R 3. Kirn, D.H. and S.H. Thorne, Targeted and
only V V + inhibitor D only V V + inhibitor D only V V + inhibitor D
60 80 armed oncolytic poxviruses: a novel
60 multi-mechanistic therapeutic class for
40
40 cancer. Nat Rev Cancer, 2009. 9(1): p. 64-71.
20 A2780
A2780-R 20 4. Horita, K., et al., lncRNA UCA1-Mediated
0
10 0 10 1 10 2 10 3 0 Cdc42 Signaling Promotes Oncolytic Vaccinia
[Doxorubicin] (nM) A2780 A2780-R
Virus Cell-to-Cell Spread in Ovarian Cancer.
Figure 1. Generation of drug-resistant ovarian cancer Figure 3. Inhibitor D enhances viral replication and Mol Ther Oncolytics, 2019. 13: p. 35-48.
cells from A2780 ovarian cancer cells OVV-mediated cell death