First-Line Combination Treatment with Low-Dose Bipolar Drugs for ABCB1-Overexpressing Drug-Resistant Cancer Populations

Sep 24, 2026

Uploaded by Miles

Tumors contain heterogeneous cell populations, including a small subset of drug-resistant cancer (stem) cells that drive recurrence after initial therapy. First-line chemotherapy can reduce tumor volume in drug-sensitive cells through apoptosis, yet it also promotes drug-resistant populations, leading to relapse and poor responsiveness to subsequent drugs. This review highlights ABCB1 (P-gp) overexpression as a key resistance feature and evaluates low-dose bipolar drugs that inhibit P-gp and sensitize resistant cells, supporting faster, clinically feasible first-line combination strategies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Keywords

1. Introduction

Tumor heterogeneity and recurrence risk

ABCB1/P-gp-mediated multidrug resistance

Rationale for P-gp inhibitor combination strategies

Figure 1. Co-treatment effects on ABCB1-overexpressing resistant cancers

Review First-Line Combination Treatment with Low-Dose Bipolar Drugs for ABCB1-Overexpressing Drug-Resistant Cancer Populations Sungpil Yoon * and Hyung Sik Kim * Citation: Yoon, S.; Kim, H.S. First-Line Combination Treatment with Low-Dose Bipolar Drugs for ABCB1-Overexpressing Drug-Resistant Cancer Populations. Int. J. Mol. Sci. 2023, 24, 8389 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24098389 Academic Editor: Cristina Marzano Received: 31 March 2023 Revised: 25 April 2023 Accepted: 5 May 2023 Published: 7 May 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea * Correspondence: [syoon88@gmail.com](syoon88@gmail.com) (S.Y.); [hkims@skku.edu](hkims@skku.edu) (H.S.K.); Tel.: +82-1055024893 (S.Y.); Fax: +82-312928800 (S.Y.) Abstract: Tumors include a heterogeneous population, of which a small proportion includes drugresistant cancer (stem) cells. In drug-sensitive cancer populations, ﬁrst-line chemotherapy reduces tumor volume via apoptosis. However, it stimulates drug-resistant cancer populations and ﬁnally results in tumor recurrence. Recurrent tumors are unresponsive to chemotherapeutic drugs and are primarily drug-resistant cancers. Therefore, increased apoptosis in drug-resistant cancer cells in heterogeneous populations is important in ﬁrst-line chemotherapeutic treatments. The overexpression of ABCB1 (or P-gp) on cell membranes is an important characteristic of drug-resistant cancer cells; therefore, ﬁrst-line combination treatments with P-gp inhibitors could delay tumor recurrence. Low doses of bipolar drugs showed P-gp inhibitory activity, and their use as a combined therapy sensitized drug-resistant cancer cells. FDA-approved bipolar drugs have been used in clinics for a long period of time, and their toxicities are well reported. They can be easily applied as ﬁrst-line combination treatments for targeting resistant cancer populations. To apply bipolar drugs faster in ﬁrst-line combination treatments, knowledge of their complete information is crucial. This review discusses the use of low-dose bipolar drugs in sensitizing ABCB1-overexpressing, drug-resistant cancers. We believe that this review will contribute to facilitating ﬁrst-line combination treatments with low-dose bipolar drugs for targeting drug-resistant cancer populations. In addition, our ﬁndings may aid further investigations into targeting drug-resistant cancer populations with low-dose bipolar drugs. Keywords: bipolar drugs; heterogeneous resistant cancer population; ﬁrst-line combination treatment; ABCB1 (or P-gp) overexpression 1. Introduction Tumors associated with poor survival comprise high-grade, metastatic, advanced, and aggressive cancers because they are difﬁcult to remove with surgery and can recur in a short time or eventually with the use of currently available chemotherapeutic drugs. These tumors include ovarian cancer, pancreatic cancer, lung cancer, glioma, and triple-negative breast cancer (TNBC) . Therefore, other treatment strategies are needed to remove the tumor or delay tumor recurrence. Tumors comprise a heterogeneous population that mainly contains chemotherapeutic drug-sensitive cancer cells. However, a small proportion of tumors are composed of multidrug-resistance (MDR) cancer cells, which include cancer stem cells (CSCs) [1,2] . A critical mechanism for evading chemotherapeutic toxicity is the overexpression of ABCB1 protein or P-glycoprotein (P-gp) on their membranes and the active pumping of chemotherapeutic drugs as substrates from cancer ce

FAQs

Why do first-line chemotherapies often lead to tumor recurrence?

They can trigger apoptosis in drug-sensitive populations but also stimulate drug-resistant cancer populations. This shift increases recurrence because recurrent tumors are primarily drug-resistant and less responsive to chemotherapy.

What role does ABCB1 (P-gp) play in drug resistance?

ABCB1/P-gp overexpression on cancer cell membranes actively pumps chemotherapeutic drugs out of cells. This reduces intracellular toxicity and supports the survival and growth of resistant tumors.

How do low-dose bipolar drugs contribute to the proposed combination treatment?

Low doses of bipolar drugs show P-gp inhibitory activity and can sensitize ABCB1-overexpressing drug-resistant cancer cells. The review argues that this enables more effective first-line combination treatment to delay relapse and reduce resistant populations.

Sep 24, 2026

Uploaded by Miles