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Review
. 2023 Mar 11:14:193-206.
doi: 10.18632/oncotarget.28382.

Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells

Mikhail V Blagosklonny  1
Affiliations
Review

Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells

Mikhail V Blagosklonny. Oncotarget. .

Abstract

Cancer therapy is limited by toxicity in normal cells and drug-resistance in cancer cells. Paradoxically, cancer resistance to certain therapies can be exploited for protection of normal cells, simultaneously enabling the selective killing of resistant cancer cells by using antagonistic drug combinations, which include cytotoxic and protective drugs. Depending on the mechanisms of drug-resistance in cancer cells, the protection of normal cells can be achieved with inhibitors of CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases. When normal cells are protected, the selectivity and potency of multi-drug combinations can be further enhanced by adding synergistic drugs, in theory, eliminating the deadliest cancer clones with minimal side effects. I also discuss how the recent success of Trilaciclib may foster similar approaches into clinical practice, how to mitigate systemic side effects of chemotherapy in patients with brain tumors and how to ensure that protective drugs would only protect normal cells (not cancer cells) in a particular patient.

Keywords: cyclotherapy; oncology; rapamycin; resistance; trilaciclib.

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Conflict of interest statement

CONFLICTS OF INTEREST

Author has no conflicts of interest to declare.

Figures

Figure 1
Figure 1. How to kill DOX-resistant cells, sparing sensitive cells.
(A) Doxorubicin (DOX) kills parental sensitive cells, sparing resistant cells. (B) At low doses, DOX (Low-DOX) causes cell-cycle arrest in parental (sensitive) cells only. (C) Paclitaxel (PTX) kills both parental and DOX-resistant cells. (D) A combination of Low-Dox and PTX kills DOX-resistant cells, sparing parental (sensitive) cells.
Figure 2
Figure 2. Caspase inhibitors (CI) selectively protect normal cells from chemotherapy-induced apoptosis, without protection multidrug-resistant cancer cells.
Flavopiridol (shown in red, as a cytotoxic/lethal drug) can induce apoptosis. The caspase inhibitor Z-DEVD-fmk (green) can block apoptosis but multidrug-resistant cancer cells pump it out.
Figure 3
Figure 3. p53-dependent and Rb-dependent cyclotherapy.
(A) p53-dependent cyclotherapy. Normal cell and cancer cells, lacking wild type p53 (p53−/−), are treated by low dose p53-inducing drugs (e.g., nutlin-3, DOX, ActD) and then treated byTaxol (PTX), which kills cells in mitosis. Protective drugs (green), lethal drugs (red). Induction of p53 causes G1 arrest and protects cells from mitosis-specific lethality of PTX. (B) Rb-dependent cyclotherapy. Cancer cells lack. Normal cells and cancer cells, lacking Rb (Rb−/−), are treated by a combination of low dose CDK4/6 inhibitor (e.g., trilaciclib, palbociclib) and DNA-damaging chemotherapy (5-FU, carboplatin, etoposide), which kill cells in S-phase. Protective drug (green), lethal drug (red). CDK4/6 inhibitor causes G1-arrest in normal cells, protecting cells from S-specific lethality of chemotherapy.
Figure 4
Figure 4. From tumor relapse to selective protection of normal cells (proposal).
(A) At therapeutic doses, palbociclib causes therapeutic response by eliminating palbociclib-sensitive (S) cancer cells. Selection for resistant cancer cells (R) leads to relapse and tumor progression. (B) Relapsed palbociclib-resistance is treated with Taxol (PTX). Palbociclib is used to protect normal cells from PTX. The cancer cells will not be protected because they are palbociclib-resistant.
Figure 5
Figure 5. Exploiting selection for resistance for (and against) nutlin-3 (proposal).
(A) Nultin-3 causes response in wt p53-expressing tumors. By killing cells with wt p53, it selects for loss of wt p53 (nutlin-3-resistance). (B) Relapsed nutlin-3-resistance tumors is treated with Taxol. Low doses of nutlin-3 are used to protect normal cells from Taxol (PTX). The cancer cells will not be protected because they are nutlin-3-resistant. A combination nutlin-3 plus PTX may selected for clones with wt p53. Then (A) repeat.
Figure 6
Figure 6. Synergistic/antagonistic combinations.
(A) Normal cell. Protecting drug antagonizes cytotoxic 1 drug. (B) Protector-resistant cancer cell. Cytotoxic drugs 1 and 2 drugs are synergistic.
See this image and copyright information in PMC

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